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Identifying the contextual enhancers in the Patient-practitioner

encounter that have therapeutic effect - Mixed methods systematic

review and Meta-analysis

Dr Ramadan Musa, Prof Michael Doherty and Dr Claire Diver and Prof Weiya

Zhang

1

Abstract

Background: Chronic painful distressing conditions such as osteoartritis are common health

problems that represent a major challenge to the National Health Service (NHS). About 15 million

people in England have chronic conditions of whom half (7.8 million) have chronic painful distressing

conditions, leading to 50 % of GP appointments and consuming 70% of the total NHS budget (DOH

report, 2012). There is no magic bullet for these conditions. Treatment largely relies on the care and

optimisation of the existing treatments. Contextual enhancement such as improvement of the

practitioner-patient relationship has been acknowledged as having an important therapeutic effect,

irrespective of any prescribed drug or treatment (Abhishek and Doherty, 2013; Zhang et al., 2008).

However, which are the key contextual enhancers that may be used to improve the treatment

benefits and hence reduce the NHS costs remains unknown.

Objective: to identify the key contextual enhancers and to develop a contextual enhancement

package (CEP).

Methods: intial Delphi exercise was carried out to identify the clinically relevant contextual

enhancers and a Mixed method systematic literature search was undertaken to identify evidence to

support the key contextual enhancers. Medline via ovid, Embase, PsycINFO, CINAHL were searched

separately. The search was not limited to a time frame, disease area or language. All studies were

included except for case reports, editorial and review articles. Adults ≥18 years old who consulted

with practitioners were eligible. Both disease-specific outcomes such as pain and symptoms, and

generic outcomes such as self-efficacy, patient global assessment and quality of life were included.

Quality of studies was assessed using the Joanna Briggs Institute Qualitative Assessment and Review

Instrument (JBI-QARI). Second Delphi exercise will be conducted in future to generate the key

contextual enhancers that have therapeutic effects, and at later stage preliminary study using survey

and interview will be conducted to examine the acceptability of the contextual enhancement

package (CEP) in clinical practice utilizing random sample of five GPs.

Results; Twenty world-renowned experts in placebo research and contextual enhancers were invited

to participate in the Delphi process (Table 3.4). 75% (15 out of 20) of the invited panel members

accepted the invitation and responded to the first round questionnaire. The responses to the first

questionnaire produced 56 items: 15 practitioner factors; 11 patient factors; 7 practitioner-patient

interaction related factors; 8 environmental factors; and 8 other factors. These factors were sent to

the panel members for ranking (see appendix 4).

87% (13 out of 15) of the panel members completed the second ranking round. The contextual

enhancers with mean ranking scores of 4 or more were accepted (total of 16) while contextual

enhancers with mean ranking scores of less than 4 were rejected (n = 8). The ranking mean was

variable depending on the importance of the contextual enhancers and was high (9.15) for

practitioner’s empathy and low (4.76) for environmental factors, see Table 3.1. The 95% Confidence

Intervals of all the responses were narrow with standard deviation (SD) between 0.5 and 3, which

indicates that if we were to ask the same question of a different sample, we would be most likely to

get a similar result.

Keywords: Contextual enhancers, placebo, practitioner-patient relationships

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Abbreviations

NHS National Health Service

GP General practitioner

QOF Quality and Outcomes Framework

OA Osteoarthritis

BC Before Christ

DOH Department of Health

CCK-A Cholecystokinin-A

PCE Proportion attributable to contextual effects

RCP Royal College of Physicians

RCT Randomized controlled trial

NCEPOD The National Confidential Enquiry into Patient Outcome and Death

CDC Centre for Disease Control (USA)

CEP Contextual enhancement package

GMC The General Medical Council

fMRI Functional magnetic resonance imaging

FEV1 Forced expiratory volume in one second

JBI Joanna Briggs Institute

JBI-QARI JBI Qualitative Assessment and Review Instrument

VAS Visual analogue scale

IBS Irritable Bowel Syndrome

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Table of Contents Abstract ................................................................................................................................................... 1

Abbreviations .......................................................................................................................................... 2

Chapter 1 Introduction ........................................................................................................................... 7

1.1 Background .................................................................................................................................. 7

1.2 Literature review ........................................................................................................................... 7

1.2.1 Prevalence of chronic health conditions ................................................................................ 7

1.2.2 The social impact of chronic health conditions ..................................................................... 7

1.2.3 The economic burden of chronic health conditions .............................................................. 8

1.2.4 Chronic painful health conditions are the biggest challenge facing the NHS ........................ 8

1.4 Contextual enhancers ................................................................................................................... 8

1.4.1 What are the Context and the Contextual enhancers? ......................................................... 8

1.4.4 Objective evidence for the healing effects of Contextual enhancers .................................. 12

1.3 Contextual enhancers and placebo effect .................................................................................. 14

1.3.1 Definition of the placebo effect: .......................................................................................... 14

1.3.2 History of Placebo effect ...................................................................................................... 14

1.4.5 Mechanism and physiology of placebo effect ..................................................................... 15

1.4.3 Negative effects of the context/placebo (Nocebo effects) ................................................. 16

1.4.7 How can we measure the magnitude of Placebo effect/Contextual effect?....................... 17

1.5 Previous systematic review on the influence of the contextual enhancers on the outcomes of

the practitioner-patient encounter. ................................................................................................. 18

1.7 Research Question ...................................................................................................................... 19

1.8 Aims............................................................................................................................................. 19

1.9 Objectives.................................................................................................................................... 19

1.10 The main outcome measures.................................................................................................... 19

1.11 Justification of this study .......................................................................................................... 19

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Chapter 2 Methods ............................................................................................................................... 20

2.1 The Delphi method ..................................................................................................................... 20

2.1.1 Use of the Delphi method to identify key contextual enhancers ........................................ 20

2.1.2 Strengths of the Delphi Method .......................................................................................... 20

2.1.3 Weaknesses of the Delphi Method ...................................................................................... 20

2.2 The Delphi study methodology ................................................................................................... 21

2.2.1 Identification of potential panel members .......................................................................... 21

2.2.2 Delphi invitation letter ........................................................................................................ 21

2.2.4 The Delphi questionnaire ..................................................................................................... 21

2.3 The Delphi process ...................................................................................................................... 21

2.4 Delphi data analysis .................................................................................................................... 22

2.4.2 Quantitative data analysis ................................................................................................... 22

2.6 The systematic review methodology .......................................................................................... 23

2.6.1 Mixed methods reviews ....................................................................................................... 23

2.6.2 The three frameworks for conducting mixed methods reviews .......................................... 23

2.6.2 Proposed search strategy..................................................................................................... 24

2.6.3 Search sources ..................................................................................................................... 25

2.6.4 Search terms ........................................................................................................................ 25

2.6.5 MeSH terms ......................................................................................................................... 25

2.6.6 Identifying and obtaining studies ........................................................................................ 25

2.7 Quality assessment ..................................................................................................................... 26

2.8 Data Extraction............................................................................................................................ 27

2.8.1 Handling missing data .......................................................................................................... 27

2.9 Data analysis ............................................................................................................................... 27

2.9.1 Qualitative Data Analysis ......................................................................................................... 28

2.9.2 Quantitative data analysis ....................................................................................................... 31

2.10 Meta-analysis ............................................................................................................................ 31

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2.10.1 Assessment of heterogeneity ............................................................................................ 31

2.10.3 Sensitivity analysis ............................................................................................................. 33

2.11 Narrative synthesis................................................................................................................ 33

2.12 Software for qualitative and quantitative data analysis ........................................................... 33

Future plan to Test CEP acceptability and credibility (Post PhD plan).............................................. 34

2.13 Methodology for study to test CEP acceptability ..................................................................... 34

Aim ................................................................................................................................................ 34

Objectives and research design .................................................................................................... 34

Chapter 3 Results .................................................................................................................................. 35

3.1 Delphi results .......................................................................................................................... 35

Table 3.1 Contextual elements included (mean score > 4) ........................................................... 36

3.2 The outcomes of four contextual enhancers searched using 4 databases ............................. 38

Table 3.2: outcomes of four contextual enhancers search .......................................................... 38

Chapter 4 Plan ....................................................................................................................................... 40

4.1 Plan for the first year, see Gantt chart appendix – 7 ........................................................ 40

[i] Conduct Delphi process to collect consensus about the important contextual enhancers ......... 40

4.2 Plan for the second year, see Gantt chart appendix -7 .................................................... 40

4.3 Plan for the final year .................................................................................................................. 40

[i] Conduct second Delphi process ................................................................................................ 40

[ii] Write up the final PhD thesis ................................................................................................... 41

4.4 Plan for the future {post PhD} ..................................................................................................... 41

[i] CEP and training: manual, courses (both face to face and online) ........................................... 41

[ii] Feasibility study for CEP through survey and interview sample of GPs to test acceptability of

CEP. ............................................................................................................................................... 41

[iii] RCT for CEP to evaluate the treatment effect of CET ............................................................. 41

Reference .......................................................................................................................................... 42

Chapter 5 appendices ........................................................................................................................... 49

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Appendix - 1 - PRISMA 2009 Flow Diagram ...................................................................................... 49

Appendix - 2 - Delphi invitation letter .............................................................................................. 50

Appendix - 3 - The Delphi questionnaire .......................................................................................... 51

Appendix - 4 – The responses of the Delphi panel members ........................................................... 52

Appendix - 5 - statistical analysis of all the Delphi responses .............................................................. 55

Appendix - 6 - Table (3.4) Name of the Delphi panel members ....................................................... 57

Appendix - 7 ...................................................................................................................................... 58

Reviw registration ......................................................................................................................... 58

Reliability and external validity ..................................................................................................... 58

Potential limitations and weaknesses of the review .................................................................... 58

Ethical considerations ................................................................................................................... 58

Dissemination ............................................................................................................................... 58

Appendix -8 -Proposed Ganttthe research project ........................................................................... 59

Appendix -9 - Table 4.2 Courses attended in the first year .......................................................... 60

Table 4.4 Numbers and dates of the supervisor’s meetings ........................................................ 60

Glossary ................................................................................................................................................. 61

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Chapter 1 Introduction

1.1 Background

Chronic conditions, especially painful distressing ones, are a common public health problem

that represents a major challenge to the National Health Service (NHS) because of their high

prevalence, chronicity and generally poor response to therapy. Most literature defines

chronic painful conditions as “ongoing symptoms lasting longer than 3 months” (Merskey

and Bogduk, 1994). They often do not respond to the usual model of care and are managed

best with a multidisciplinary approach, requiring good care, support and excellent

communication skills, an examples of chronic painful conditions are osteoarthritis,

fibromyalgia and irritable bowel syndrome (Merskey and Bogduk, 1994; Donaldson, 2009).

1.2 Literature review

1.2.1 Prevalence of chronic health conditions

Data from the 2012 Quality and Outcomes Framework (QOF) and the 2009 General Lifestyle

Survey suggest that around 7.8 million people in England have chronic painful conditions out

of a total of 15 million people with chronic health conditions, with 5 million of these

reported to have chronic musculoskeletal conditions (DOH report, 2012), while in the USA

about half of all adults (i.e. 117 million people) had one or more chronic health conditions

(Ward et al., 2014). Moreover, the prevalence of chronic conditions is rising with the ageing

population and improved earlier diagnosis (Donaldson, 2009).

Osteoarthritis(OA) is an example of a chronic health condition which can be painful and

distressing. It is the most common form of arthritis and one of the leading causes of

disability worldwide and has no curative treatment (Ezzo et al., 2001; RCP 2008;

Manheimer et al., 2010). In the UK around a third of people aged 45 years and over,

estimated to be 8.75 million people, have sought treatment for OA and this figure is likely to

increase due to an ageing population (Arthritis Research UK, 2009; Bhatia et al., 2013).

1.2.2 The social impact of chronic health conditions

Chronic health conditions are a major public health challenge and one of the most common

reasons for which people seek medical consultation, especially because of pain and distress.

It is estimated that people with chronic painful conditions consult their doctor up to five

times more frequently than others. This equates to almost 5 million GP appointments a year

(Elliott et al., 1999). Chronic painful conditions have a significant impact on people’s lives,

as they are associated with a number of negative outcomes including depression, job loss,

reduced quality of life, impairment of function and limiting of daily activities (Donaldson,

2009).

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1.2.3 The economic burden of chronic health conditions

In the UK, treatment and care for people with chronic health conditions is estimated to

consume around £7 in every £10 of the total NHS budget (DOH report, 2012), while in the

USA, chronic health conditions account for around 86% of the nation’s health care costs

(CDC report, 2016). People with chronic painful health conditions now account for about 50

per cent of all GP appointments, 64 per cent of all outpatient appointments and over 70 per

cent of all inpatient bed days (DOH report, 2012; Barnett et al., 2012). Moreover, in the UK,

the economic burden of OA alone is substantial both in terms of direct costs (such as drugs,

hospital care) and indirect costs (such as loss of productivity). Between 1999 and 2000

about 36 million working days were lost due to absence from work, leading to productivity

losses estimated at £3.2bn (€3.8bn, $5.1bn), with the total cost to the UK economy being

estimated at 1% of gross national product per year (RCP, 2008; Bitton, 2009).

1.2.4 Chronic painful health conditions are the biggest challenge facing the NHS

The UK Department of Health annual report for 2012 suggests that the number of people

with chronic painful health conditions appears to be rising, which will have a significant

impact on health and social care and may require £5 billion in additional expenditure by

2018. Miles Ayling, the director of Innovation and Service Improvement at the Department

of Health, stated, “The increasing prevalence of chronic health conditions is the biggest

challenge facing the NHS now and for the future and plans need to be put in place now to

address the growing needs of these people with chronic painful health conditions” (DOH

report, 2012). The NHS has a strong mandate to make efficiency savings, so focusing on

effective management of chronic painful health conditions could offer an excellent

opportunity for substantial savings for the NHS in the future (DOH report, 2013).

Creating contextual enhancers package (CEP) can form powerful therapeutic tool for

management of the chronic painful condition and hence reduce the NHS costs (Abhishek

and Doherty, 2013; Zhang et al., 2008).

1.4 Contextual enhancers

1.4.1 What are the Context and the Contextual enhancers?

The word context is derived from the Latin “contexture” meaning “to weave together” and

the term “contextual enhancers/healing” was introduced by Kaptchuk, in 2008, to describe

the benefits resulting from the clinical encounter which are attributable to the causal

connection between practitioner–patient interaction (or a particular component of the

interaction) and lead to improvement in the condition of the patient. The participants

(patients, practitioners, family members of the patient, and nurses) form part of the context

(Miller and Kaptchuk, 2008), see figure 1.4.1, and figure 1.4.2.

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Contextual enhancers (e.g the clinical setting, the patient’s expectations, the style of the

practitioner and the ritual of administering treatment) enhance the healing of patient

through the context of the clinical encounter, as distinct from the treatment interventions,

see figure 1.4.1 and figure 1.4.2.

Figure 1.4.1, showing the practitioner-patient interaction and the contexual enhancers

1.4.2 the constituents of the contextual enhancers

Contextual enhancers can be divided into: (i) practitioner characteristics, such as being

empathetic, warm, attentive, confident, and optimistic, (ii) patient characteristics, such as

expectation, personality factors and patient’s illness perceptions; (iii) intervention

characteristics, such as reputable brand, higher cost, greater number of tablets and colour

of tablets; and (iv) environment characteristics such as health care equipment and settings.

(Abhishek and Doherty, 2013), see figure 1.4.2, the following are examples,

(i) Practitioner characteristics

These include the doctor’s charming smile and professional clothes or white coat, empathy

and attitudes. For example, empathetic practitioner understands what the patients are

feeling because he or she has had a similar experience and are able to relates to a patient

which can have positive imapct on the patient’s feelings and outcome. Studies confirm that

a warm consultation provided by a confident practitioner, who is perceived as competent by

the patient, not only improves outcomes but also forms an important early determinant of

patient confidence, trust and satisfaction (Petrilli et al., 2015).

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Figure 1.4.2, showing the contexual enhancers

In the “Good medical practice” booklet published by the GMC, regarding “what makes a

good doctor”, Sister Donna Keenan (Northern Ireland Nurse of the Year 2010) states: “The

essential ingredients for the making of a good doctor are being approachable, confident,

decisive, intelligent, interested, compassionate and caring - being able to absorb people's

pain and anxieties without losing focus, treating patients as a human being rather than a

symptom or collection of symptoms” (GMC, 2013p1).

(ii) Patient characteristics, the following are examples:

(a) Patient expectation. This refers to the anticipation of what is to be encountered in the

consultation or the healthcare system. Understanding and managing patient expectations

can improve patient satisfaction, which refers to the fulfilment or gratification of a desire or

need. Patients with unmet expectations may not return for follow-up care and his/her

chronic painful condition might become exacerbated or may complain to the physician (Hoy,

2008; Farooqi, 2005).

In 2011 Bingel and colleagues conducted a study to explore the patient’s expectations in

which they used functional MRI (fMRI) to record brain activity to corroborate the effects of

“patient’s expectations” on the analgesic efficacy of remifentanil (opioid analgesic) and to

elucidate the underlying neural mechanisms. They found that positive treatment expectancy

substantially enhanced (doubled) the analgesic benefit of remifentanil, while negative

treatment expectancy abolished the analgesic effect (Bingel et al., 2011), Table 1.4.2.

Table 1.4.2, showing results from the Bingel et al. (2011) study.

Drug Analgesic treatment (remifentanil) was given to 3 groups of patients

Patients Group (1) Group (2) Group (3)

Information None Positive Negative

Expectancy No expectations of an analgesic effect

Positive expectancy of improved analgesic effect

Negative expectancy of exacerbation of the pain

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Placebo effect

Minimum or no placebo effect

Analgesic effect was enhanced in the positive information condition

Negative information abolished the effect of the analgesic treatment

Neural effect

Drug effects only Enhanced efficacy of the drug therapy

Negative expectations block the efficacy of the analgesic treatment

Kirsch, in 2008, published a landmark study on the new antidepressants drug which showed

that “negative expectations” can affect the patient’s response to treatment. He reviewed

all the published and unpublished data related to the new antidepressent drug and

performed meta-analytic techniques to assess linear and quadratic effects of initial severity

on improvement scores for drug and placebo groups and on drug–placebo difference scores,

which make this study very robust (Kirsch et al., 2008). He found that the new-generation

antidepressants drug did not produce clinically significant improvements in moderately

depressed patients compared with the placebo. A significant effect was found only in the

most severely depressed patients, and among these patients the effect seemed to be due to

decreased responsiveness to the placebo, rather than increased responsiveness to the drug.

The explanation suggested was that the most severely depressed patients had “negative

expectations” regarding offered drug, which blocked the placebo effect (Kirsch et al., 2008).

(b) Patient beliefs and illness perceptions

Patients’ negative “illness perceptions” towards treatment can contribute to negative

treatment outcomes on the otherhand positive perceptions can contribute to an enhanced

treatment outcome. Recent studies in primary care highlight the importance of patients’

beliefs about their illness as being important in influencing their “satisfaction with the

consultation” (Petrie, Jago and Devcich, 2007).

(iii)The practitioner-patient interactions

The practitioner-patient relationship has been acknowledged as having an important

therapeutic effect, irrespective of any prescribed drug or treatment (Abhishek and Doherty,

2013; Zhang et al., 2008). This relationship with the patient can be built through a smile,

handshake, and warm reception. The National Confidential Enquiry into Patient Outcome

and Death (NCEPOD) report in 2009 found that poor communication with patients and

colleagues was a factor in 13.5% of 1983 patients’ deaths within four days of hospital

admission (NCEPOD, 2009). In 2008, a review of patient safety events in clinical practice

found that communication failure was a factor in 13% of reported clinical errors, with 70%

related to healthcare professional interactions with patients (Makeham et al., 2008). In fact,

between 40% and 80% of the therapeutic effect in any condition can be explained by the

practitioner-patient interactions (Watson et al., 2012).

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(iv) Health care setting

These can be the actual physical space of the practice or surgery, the waiting room and the

consultation room, the type of furniture and equipment but also include the people within

this space, in particular the receptionists and the nurses. The patients expect the

receptionist to welcome and greet them in a pleasant manner and the waiting room to be

well managed, comfortable, friendly, to have an appropriate temperature (not too cold or

too hot), to be clean and tidy with comfortable seats and to offer activities for patients

while they wait (e.g. reading materials, children’s toys) (Bowling et al., 2012).

1.4.4 Objective evidence for the healing effects of Contextual enhancers

There are several studies which support the objective effect of the contextual enhancers.

For example, a study published in the New England Journal of Medicine compared the

response of 39 volunteers with asthma to albuterol, an inhaled bronchodilator used to treat

asthma, with two different inactive treatments, a placebo inhaler and sham acupuncture

(Wechsler et al., 2011), see the figure 1.4.4-a.

Figure 1.4.4-a, comparing the effect of placebo with albuterol, an inhaled bronchodilator

used to treat asthma.

Forced expiratory volume in one second (FEV1), an objective test of lung function was used

to measure the response of the volunteers to different types of therapy. The study showed

that albuterol was more effective than both the placebo inhaler and sham acupuncture but

when the volunteers were asked about their perceived improvement in asthma’s

symptomes, they stated that both albuterol and the placebos were both beneficial

(Wechsler et al., 2011).

In 1995, Benedetti et al. conducted a clinical study, performed on patients who underwent

chest surgery (thoracotomy), examining the effects of proglumide, a glutamic acid

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derivative with a weak but selective affinity for the Cholecystokinin-A (CCK-A) receptors

which has been shown to potentiate the effect of endogenous opioids through the

blockade of CCK receptors in the brain (Benedetti et al., 1995; Benedetti, 1996), see figure

1.4.4-b.

The study included the following three arms: (1) a no-treatment group to monitor the

normal course of pain; (2) several hidden-injection conditions in order to rule out possible

analgesic effects of proglumide; and (3) different doses of proglumide (Benedetti et al.,

1995). After recovery from anaesthesia the patients were treated with saline solution or

proglumide.

Figure 1.4.4-b, comparing the effect of proglumide, Cholecystokinin-A (CCK-A) antagonist

with placebo.

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The above figure 1.4.4-b, shows that the hidden injection of three different doses of

proglumide 0.05, 0.5 and 5 mg had no effect on the time course of pain compared with the

no-treatment group, indicating that proglumide by itself had no analgesic effects and did

not interact with the anaesthetic agents used for surgery. However, when an open

injection of saline solution was performed and the patients were told that it was a potent

painkiller, a moderate placebo effect was observed. Nonetheless, an enhancement of the

placebo response only occurred if the open injection contained either 0.5 or 5 mg of

proglumide, whilst the 0.05 mg dose was ineffective (Benedetti et al., 1995).

The placebo effect can be modulated in two opposite directions - it can be partially

abolished by naloxone and potentiated by proglumide (Benedetti, 1996). The placebo

potentiation by proglumide occurred only in placebo responders and not in placebo non-

responders, suggesting that activation of the endogenous opiate system is a necessary

condition for the action of proglumide (Benedetti, 1996).

1.3 Contextual enhancers and placebo effect

1.3.1 Definition of the placebo effect: “any effect attributable to a pill, potion, or

procedure, but not to its pharmaco-dynamic or specific properties” (Wolf S., 1959).

Contextual enhancers cover all factors which have therapeutics effect on the patient, so the

contextual enhancers encompasses the placebo effects, see figure 1.3.1 below.

1.3.2 History of Placebo effect

The effect of placebo has been well known since the time of Socrates (Greek philosopher

470 BC) but the scientific terminology and its connection with medicine appeared later,

around 1785, see Table 1.3.2.

Scientific interest in the placebo effect has risen considerably over the last forty years; the

number of citations listed on PubMed for ‘the placebo effect’ has increased from 214 in the

1970s to 74514 at the present time. The neurobiology of the placebo effect was born in

1978, when it was shown that placebo analgesia could be blocked by the opioid antagonist

naloxone, which indicates an involvement of endogenous opioids (Levine et al., 1978). The

Therapeutic

Practitioner-

patient interaction

Practitioner

factors

Setting

factors Patient

Context enhancers

Placebo form part of

contextual enhancers placeb

o

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leading rationale for research on placebo effect is to harness the power of placebo effect to

enhance therapeutic outcomes in clinical practice.

Table (1.3.2) History of Placebo

Date Term used Notes

Since 1785 “Thomas Jefferson”

“I will please” Thomas Jefferson (1743-1826) “one of the most successful physicians I have ever known has assured me that he used more bread bills, drops of coloured water, and powders of hickory ashes, than of all other medicines put together.”

(1945 -) “John Haygarth”

“Nuisance” in RCTs Placebo was first used as a standard control in an RCT to confirm the effect of streptomycin in TB (Tuberculosis) (unpublished)

(1955 -) “Henry Beecher”

Power of “nothing” placebo response non-specific effect contextual healing/effect

Henry Beecher’s “The powerful placebo” found an average of 35% placebo responders in different conditions via a prototype of meta-analysis of 15 trials

(2000s -) “Kaptchuk”

Contextual enhancement

The placebo is a methodological tool for understanding contextual healing but is not itself responsible for clinical effects that emanate from the clinician–patient relationship.

1.4.5 Mechanism and physiology of placebo effect

A study by Kirsch et al. in 2010 showed that the brain releases natural pain-relieving

endogenous opioids called “endorphins” when people enrolled in pain studies are given

placebos, see figure 1.4.5.

fMRI was used to compare the celebral activity response to proglumide, Cholecystokinin-A

(CCK-A) antagonist with the effect of placebo (Benedetti et al., 1995; Benedetti, 1996).

Figure 1.4.5-a, using fMRI to compare the cerebral activity response to placebo and Opioid

therapy

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Patients with Parkinson’s disease who respond to placebo demonstrate increased dopamine

in the dorsal striatum, as do patients with Parkinson’s disease who respond to L-dopamine

therapy. Interestingly, patients with Parkinson’s disease treated with placebo also produce

increased dopamine in the ventral striatum regardless of whether their symptoms improve

or not (De la Fuente-Fernández et al., 2004, 2006).

A study performed in healthy volunteers using fMRI, naloxone and saline has shown that

placebo is associated with increased activity in cortical areas such as the dorsolateral

prefrontal cortex and orbitofrontal cortex, which may be associated with expectations of

pain relief, see figure 1.4.5-b (Wager et al., 2004). Recently, it was shown that non-opioid

mediated placebo analgesia effects in healthy volunteers can be blocked by the cannabinoid

antagonist rimonabant (Benedetti et al., 2013). Studies employing fMRI also have observed

increased dopamine release in areas such as the nucleus accumbens, typically related to

processes of reward and motivation, during placebo administrations in healthy volunteers,

which is likely to be related to the anticipation of a treatment effect (Scott et al., 2007).

Figure 1.4.5-b, using fMRI to compare the cerebral activity response to naloxone and saline

Moerman in 2002 published an article suggesting replacement of the term “placebo effect”

with the term “Meaning effect/response” because he suggested that it is the patient’s

interpretation of the placebo action that produces the beneficial outcome, not the actual

inert substance. For example, the brand-named analgesic was more effective than the plain

unbranded form and the same brand-named placebo was more effective than its unbranded

form (Moerman and Jonas, 2002).

1.4.3 Negative effects of the context/placebo (Nocebo effects)

Context can have either therapeutic (enhancer effects) or adverse effects (nocebo effects),

for example patients can experience side effects of a placebo tablet when they expect

negative effects, for example in a study of benign prostatic hypertrophy treated with

finasteride patients informed of the sexual side effect of finasteride reported sexual side

effects three times more often than patients who were not informed. Also research

reviews have estimated that 4-26% of patients who are randomly assigned to placebos in

trials discontinue their use because of adverse effects and that this could relate to the

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background incidence of upsets from previous experience, (e.g. if patients told they will

develop a stomach upset because of NSAID then they are more likely to develops GI side-

effects of NSAID). This indicates the need to find a balance between full disclosure of

potential adverse effects of drugs and the desire to avoid inducing nocebo effects

(Montgomery G. H. and Kirsch I., 1997).

1.4.7 How can we measure the magnitude of Placebo effect/Contextual effect?

In the randomized placebo controlled trial the overall measurable effects (the desired

outcome) are not simply additive effects of the active treatment and the placebo effect

(Beecher HK., 1955). The placebo effect is the proportion attributed to contextual effect

(PCE) out of the total effects, see figure 1.4.6.

In meta-analysis of randomised controlled trials study conducted at Nottingham university

they found the majority 75% (PCE=0.75, 95% CI 0.72 to 0.79) of the overall treatment effect

in OA RCTs is attributable to contextual effects rather than the specific effect of treatments,

see figure 1.4.6.

Figure 1.4.6, showing the overall treatment effect and the proportion attributable to

contextual effect (PCE) for pain in osteoarthritis.

1.4.9 Ethical consideration of placebo and contextual enhancers

The traditional use of placebos in clinical practice has been criticized from an ethical

perspective as deceptive, thus infringing patient autonomy and compromising informed

consent (Brody H., 1982). How can a physician administer a substance or perform ritual

known to have no specific effect on the patient’s condition? This ethical problem has been

faced by numerous physicians. However, although the use of placebos necessarily involves

some degree of deception the physician’s purpose is not actually to deceive the patient, but

to cure.

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In 2010, Dr. Ted Kaptchuk, director of the Harvard placebo program, undertook an “open-

label” placebo study on irritable bowel syndrome in which patients were told they were

taking a placebo and that the placebo effect was powerful and had mind-body effects. He

found that the declared placebo still produced a placebo effect and was about 20% more

effective than treatment. However, this study was criticized because the information

delivered to the patient suggests to the patient that the placebo will have curative effect

and therefore contains a degree of deceit (Kaptchuk et al., 2010).

1.5 Previous systematic review on the influence of the contextual enhancers on the

outcomes of the practitioner-patient encounter.

Di Blasi et al. conducted a systematic review in 2001 on the influence of contextual factors

on the outcomes of the practitioner-patient encounter. Of the 25 trials they identified,

about half produced evidence of positive effects on patients’ health status after

manipulation of the practitioner-patient relationship. They also found that a positive

consultation produced the most consistent effects and that practitioners who attempted to

form warm and friendly relationships with their patients and reassured them that they

would soon get better were more effective than practitioners who kept their consultations

impersonal or formal. They concluded that further studies were needed to determine the

contextual enhancers which have therapeutic effect on the practitioner-patient encounter.

As the review conducted by Di Blasi (2001) is now 15 years old an updated review is needed

(Di Blasi et al., 2001).

1.6 Summary

Chronic conditions, especially painful distressing ones such as osteoarthritis are a growing

public health problem with huge social, medical and financial implications (Department of

Health, 2012). There is a substantial evidence that contextual enhancers can improve

practitioner-patient encounter outcomes and form cheap and effective methods for

management of chronic painful conditions (Abhishek and Doherty, 2013). The aim of this

review is to identify those contextual enhancers by conducting a mixed method systematic

review using data from both qualitative and quantitative studies.

The traditional systematic reviews use a statistical meta-analysis to synthesize the effect

sizes of randomized controlled trials and then provide a forest plot to show the overall

pooled effect and thereby answer the question of “effectiveness of an intervention” or

“which interventions work”? However in areas of human interaction we need to look into

the details of practitioner-patient interaction and why it works and how it works and for

whom? This requires a novel approach of mixed methods systematic review using a

combination of quantitative and qualitative research data, the results of which would be of

particular importance for clinical practice and public health policymakers.

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1.7 Research Question

Identifying contextual enhancers in the Practitioner-patient encounter that have therapeutic

effect in chronic conditions – Mixed methods systematic review and Meta-analysis.

1.8 Aims

(i) To identify contextual enhancers which have beneficial therapeutic effects.

(ii) To evaluate the effectiveness of those contextual enhancers in the management of

chronic painful conditions such as osteoarthritis.

(iii) To develop a universal contextual enhancement package (CEP) based on the identified

contextual enhancers.

1.9 Objectives

(i) Conduct a Delphi consensus process to identify the opinions of an expert panel about

contextual enhancers and use these as a tool to develop systematic review search strategy.

(ii) Develop a search strategy to identify qualitative studies (interviews, focus groups) and

quantitative studies (e.g. RCTs) to determine the contextual enhancers.

(iii) Conduct data analysis of the identified articles to evaluate the effectiveness of those

contextual enhancers in the management of chronic painful conditions such as

osteoarthritis and draw conclusions from the data to develop a universal contextual

enhancement package (CEP).

The above objectives (i to iii) will be completed in three years of my PhD. Afterwards, I

would like to move into; Conduct a preliminary study to assess the acceptability and

practical application of the CEP through an interview with a small sample of GPs. And also

conduct the feasibility study for CEP and a randomised controlled trial to evaluate the

efficacy of CEP in OA and other chronic painful destressing conditions.

1.10 The main outcome measures

Disease-specific outcomes such as pain measured by VAS and generic outcomes such as

self-efficacy, patient global assessment and quality of life.

1.11 Justification of this study

(i) This study will contribute to production of a CEP to improve management of chronic

painful and distressing conditions.

(ii) Hopefully this study will help influence guidelines for management of other chronic

painful distressing conditions such as depression and IBS.

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Chapter 2 Methods

2.1 The Delphi method

2.1.1 Use of the Delphi method to identify key contextual enhancers

The Delphi process aims to determine the extent to which a panel of experts agree or

disagree about a given issue and with each other to achieve a consensus opinion; It is an

inexpensive decision-making process using inductive thinking or a “bottom up approach”,

whereby the initial opinions of experts facilitate generation of an initial hypothesis, with

further formulation leading to conclusions (Salcido, 2016). it is usually conducted through

questionnaires and feedback via a number of rounds, with the ideas being refined during

each round until the final opinion is achieved (Fontana and Frey, 1994).

Historically the Delphi methods were developed in 1963 by Dalkey and Helmer, at the Rand

Corporation. The name originates from ancient Greek mythology. The Oracle of Delphi was a

person (the Pythia) considered to provide wise counsel or prophetic predictions of the

future inspired by the gods at the temple of Apollo (Dalkey and Helmer, 1963; Habibi, 2014).

The panel members are known to the researcher and to one another but their judgements

and opinions remain strictly anonymous and they can thus present and react to ideas

unbiased by the pressures of other members (Miller et al., 1993; McKenna, 1994). A

response rate of 70% was suggested by Sumsion (1998) to maintain the rigour of the Delphi

methods for each round and to achieve this score researchers must know the identity of

respondents, and non-respondents can then be persuaded gently to respond.

2.1.2 Strengths of the Delphi Method

Opinions of geographically dispersed experts can be brought electronically together while

maintaining the anonymity and confidentiality of their responses. The experts’ opinions can

be condensed into a few precise and clearly defined statements with no peer pressure. It is

cost effective with potential to gain useful information (Dunham, 1998).

2.1.3 Weaknesses of the Delphi Method

There are no guidelines to determine consensus, the process is time consuming and

participants need high commitment and motivation. The process does not cope well with

widely differing opinions or large changes in opinions and the researcher’s view may

dominate in the analysis. Success of the method depends on the quality of the participants.

There are concerns about the reliability of the technique because of drop-out and response

rates which are in part dependent on speedy responses by busy experts (Linstone and

Turoff, 2004).

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2.2 The Delphi study methodology

2.2.1 Identification of potential panel members

Delphi panel members were chosen because they are experts in the field of contextual

enhancers, or have been nominated by one of the already selected panel members (Salcido,

2016). NHS England has recently stressed the importance of the patient’s perspective so we

also included patients in the Delphi process in order to explore the patient-centred health

service approach (National Quality Board, January 2015).

2.2.2 Delphi invitation letter

A personalized invitation letter (Appendix - 2) was sent via email to all panel members, who

were asked to respond as soon as possible, preferably within two weeks. A Delphi

questionnaire was then sent via email to each panel member who accepted the invitation

and they were given two weeks to return it. Gentle reminders were sent to those who did

not return the completed questionnaire within two weeks (Habibi et al., 2014).

2.2.4 The Delphi questionnaire

The Delphi questionnaire (Appendix - 3) consists of carefully selected questions asking the

panel members to identify contextual enhancers (Ali, 2005). The questionnaire contains four

subheadings - practitioner factors, patient factors, environmental factors and practitioner-

patient interaction related factors - with one example in each subheading for the panel

members to use as guidance in their response, and spaces to fill in the answers. In addition,

there was a section for any extra comments.

2.3 The Delphi process

Round one began with the sending of a questionnaire to the invited panel members who

agreed to participate in the Delphi process (Powell, 2003). The panel members were allowed

complete freedom in their choice of contextual enhancers that they thought are most

influential (Powell, 2003). It is recommended that panel members be asked for at least five

opinions since several panel members are likely to raise the same issue using different terms

(Schmidt, 1997).

The panel members were asked to email their responses to the researcher, then all the

responses were collated to form an initial list of contextual enhancers for consideration.

When several different terms were used for what appeared to be the same issue the items

were grouped together in an attempt to provide one universal description. These

descriptions and groups of items were verified by the supervisors to ensure that the data

were fairly analysed. No items were added or omitted during analysis and the wording used

by the panel members was used as much as possible for round two (Powell, 2003).

22

The list was then sent back to the panel members individually to score in terms of priority

from 0 (not important) to 10 (most important). Normally this process is ongoing until no

further consensus can be reached but because the project was interested only in identifying

the contextual enhancers the Delphi process was concluded at the end of round two.

Contextual enhancers with mean scores of 4 or more were accepted and used as search

terms for conducting the systematic review, while items with scores of less than 4 were

rejected (Powell, 2003). The information from the ratings of the items in round one were

subjected to analysis to produce statistical summaries for each item, including means,

standard deviation and 95 confidence interval.

2.4 Delphi data analysis

The process of data analysis started from round one with all the information in the returned

questionnaires being transferred into a master table (Appendix - 4). The researcher

reordered the data generated in round one and restructured the statements to be included

in round two from the round one response but in round two only the Panel members were

judging items, not the researcher (Powell, 2003). The second round data were analysed to

identify changes in respondents’ opinions (Powell, 2003). A coding system was devised to

track each response and each response was anonymized and allocated a code for computer

storage in a digital file to facilitate data analysis (Denzin and Lincoln, 1994).

2.4.1 Qualitative data analysis

Thematic analysis was performed on all respondent data to identify key patterns, followed

by category generation and then structuring of the categories into themes. These themes

were grouped together under one heading and given certain names (e.g. practitioner’s

empathy) (Denzin and Lincoln, 1994; Bradley et al., 2007).

2.4.2 Quantitative data analysis

Descriptive statistics: the generated data from the ratings of the items in each Delphi round

were subjected to quantitative analysis by producing statistical summaries for each item,

including central tendencies (means) and levels of dispersion (standard deviation and 95

confidence intervel) to provide participants with information about the collected opinions.

This enabled the participants to see where their response stood in relation to those of the

other members.

2.5 Delphi outcome, included in the result chapter, Table 3.1, 3.2, and 3.3.

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2.6 The systematic review methodology

2.6.1 Mixed methods reviews

Systematic reviews which use only quantitative method provide statistical and theoretically

reproducible evidence. However, such evidence often ignores the patient’s opinion and the

contexts in which such evidence was drawn whereas a more comprehensive systematic

review (Mixed methods reviews) involving both quantitative and qualitative studies can

produce a wider picture and more comprehensive conclusions. There are three general

frameworks for conducting Mixed methods reviews (Sandelowski et al., 2006);

2.6.2 The three frameworks for conducting mixed methods reviews

(i)-Segregated methodologies: maintain a clear distinction between quantitative and

qualitative evidence and require individual syntheses to be conducted prior to the final

“mixed method” synthesis; the final findings may either support each other (confirmation)

or contradict each other (refutation), or they may simply add to each other

(complementary).

REVIEW question

Searching, screening, and mapping

Quantative studies Analysed separately

Qualitative Studies Analysed separately

Final mixed method synthesis

Quantative and Qualitative Studies

Figure 2.6.2-a shows the segregated methodologies for mixed methods systematic review

(ii) Integrated methodologies: combine both forms of data into a single mixed method

synthesis, usually used if both quantitative and qualitative data are similar enough to be

combined into a single synthesis. This represents the only method whereby both forms of

data can be assimilated into a single synthesis, and requires that either (a) quantitative data

are converted into themes, codified and then presented along with qualitative data in a

meta-aggregation, or (b) qualitative data are converted into numerical format and included

with quantitative data in a statistical analysis.

REVIEW question

Searching, screening, and mapping

Quantative + Qualitative studies

Analysed together

Final mixed method synthesis

Quantative and Qualitative Studies

24

(iii) Contingent methodologies: involve two or more syntheses conducted sequentially based

on results from the previous synthesis. The process begins by asking a question and

conducting a qualitative and/or quantitative synthesis. The results of this primary synthesis

generate a second question, which is the target of a second synthesis, the results of which

generate a third question and so on. Contingent designs can include either integrated

and/or segregated syntheses, and multiple syntheses can be conducted until the final result

addresses the reviewer’s objective, see the figure 2.6.2 below

REVIEW question

Searching, screening, and mapping

First Synthesis Second Synthesis

Quantative studies

Qualitative Studies

Third (the collective) Synthesis

Quantative and Qualitative Studies

Figure 2.6.2-b, showing the contingent methodologies for mixed methods systematic review

The Joanna Briggs Institute (JBI) and the International Mixed Methods Reviews

Methodology Group (IMMR), in 2012, both recommended the segregated approach to

mixed methods synthesis as described by Sandelowski et al. (2012). In this study segregated

methodologies will be used.

2.6.2 Proposed search strategy

The results of the Delphi exercise were used as terms for the search across four major

databases (MEDLINE via OvidSP, EMBASE, CINAHL and PsycINFO). The reference list of all

identified reports and articles was used to search for additional studies. The search was not

limited to a time frame or language. The inclusion and exclusion criteria are listed in Table

2.6.2, according to eligibility criteria based on PICO search criteria

Table 2.6.2, illustrating the PICO component of the search question

Inclusion criteria Exclusion criteria

Population Adult men and women aged ≥18 years and diagnosed with a chronic condition such as osteoarthritis (as defined by WHO criteria), include patients already receiving treatment and those who are not.

Younger patients <18 years and those with impaired cognitive status would be excluded.

Intervention Contextual enhancers producing beneficial effects

Any therapy other than contextual enhancers

25

Comparison Active treatment and control (no treatment) as compared to improvement achieved through contextual enhancers

Contextual or placebo therapy/effects

Outcomes Disease-specific outcomes such as pain, and generic outcomes such as self-efficacy, patient global assessment and quality of life.

Outcomes not achieved through contextual/placebo effect

Study design

All published studies (RCT, control trial, observation trial, cohort studies, qualitative and quantative studies, case control studies).

The non-published studies will be excluded along with economic related studies and case reports.

2.6.3 Search sources

Databases MEDLINE via OvidSP, EMBASE, CINAHL, PsycINFO and Dissertation Abstracts were

searched thoroughly until August 2016, (final year catch-up search will be done). The

references in the extracted studies will also be searched for any other articles. There will be

hand searching of key journals and conference proceedings, citation searching.

2.6.4 Search terms

Search terms used are the terms identified by the Delphi process, Table 3.1, and include for

example: practitioner’s empathy, patient’s expectation, and patient-practitioner

interaction/encounter.

2.6.5 MeSH terms

MeSH terms will be used in the search as shown in Table 2.6.5. In addition, Quotation Marks

will be used to refer to combined terms like "patient-practitioner interaction" and the

truncation character (*) will be used to search different word endings, such as empathy* or

empathetic*, and different terms will be combined using Boolean operators.

2.6.6 Identifying and obtaining studies

Initially, selection will centre on article titles and abstracts only, and be based on inclusive

and exclusive criteria, Table 2.6.2, removing duplicated articles. The second selection

process will be based on the full papers and all excluded articles will be listed with the

reason for exclusion. In addition, a PRISMA flow chart will be constructed to demonstrate

this process. This process of check and selection will be carried out by two reviewers, first by

me and I will then ask the supervisor to recheck the random sample to minimize error and

bias.

26

Table 2.6.5: example of search strategy

Database searched

Ovid MEDLINE 1946 to present

Search criteria

Adult 19 and plus, Human, 1946 to present

Contextual enhancers

(Practitioners patient interaction)

(SPICE) String 1 Setting

String 2 Population

String 3 Intervention

Search Terms and Number of citations

Practitioner (13071) Physician (11496) Nurse/nurse practitioners (9763)

Patient (5473)

Physician-Patient Relations/physician patient interaction (17858 Practitioner patient consultation (2) Medical consultation (760)

Boolean operator (or)

(13071) or (11496) or (9763) = 32139

5473 (17858) or (2) or (760) = 18544

Boolean operator (and)

(32139) and (5473) and (18544) = 156

2.6.7 Study selection for qualitative & quantative data

Electronic citations will be downloaded and saved into Endnotes reference manager. Titles

and abstracts will be examined carefully for any potentially relevant studies and duplicate

citations will be removed. The potentially relevant studies will be sourced as full text. Any

studies reported in abstract form only (e.g. conference abstracts) or with their full text not

available will be included only if the abstract contains sufficient information. Non-English full

text studies will be included only if an English language abstract and/or tables report

adequate information for inclusion. Studies that are not available via Nottingham University

and cannot be obtained from the British Library will be excluded.

The review will be undertaken in accordance with the general principles suggested in the

Joanna Briggs Institute database and the Preferred Reporting Items for Systematic Reviews

and Meta-Analyses (PRISMA). The relevant studies that fail to meet the inclusion criteria on

full text inspection and relevant studies that cannot be obtained will be recorded with the

reasons for exclusion.

2.7 Quality assessment

Selected papers for retrieval will be assessed by two independent reviewers. They will first

be reviewed by me and I will then ask the supervisor to recheck to minimize error and bias

and for methodological validity and any disagreements that arise between the reviewers will

be resolved through discussion, or with a third reviewer, prior to inclusion in the review,

27

using standardized critical appraisal instruments. Qualitative data will be assessed by the

Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI), accessed

online at (http://www.jbiconnect.org/sumari/qari/common/login.cfm), and quality

assessment will be based on questions with the answers (Yes), (No), (Unclear), and (Not

applicable). The quantitative data, such as the RCTs, will be assessed by the Cochrane risk

of bias criteria to categorize them into ‘high risk’, ‘low risk’ or ‘unclear risk’, addressing the

following specific elements: sequence generation; allocation concealment; blinding of

participants and personnel; method of randomization; blinding of outcome assessment; and

incomplete outcome data and selective outcome reporting (withdrawals/dropout) (Higgins

et al., 2011; JBI, 2014).

The Cochrane collaboration appraisal tool and the Joanna Briggs Institute Qualitative

Assessment and Review Instrument (JBI-QARI) were chosen because they have both been

validated and are commonly used effective and comprehensive tools for assessing the

quality of mixed methods studies. A table will be constructed to compare the quality of the

included studies based on the above criteria (Higgins et al., 2011).

2.8 Data Extraction

The JBI-QARI standardized data extraction tool will be used for both Qualitative and

Quantative data. The data extracted from the selected articles will be presented in four

tables.

Table 1: The participants’ characteristics and study identification information which

includes: Author, year, full-text/abstract, country, sample size, age, sex, height and weight.

Table 2: The details of the intervention; types of consultation, practitioner-patient

relationship and the setting.

Table 3: The different outcome measures such as the health status of the patient or his/her

feedback.

Table 4: The characteristics of the study such as country, RCT, Blind or open, year of

publication, etc.

2.8.1 Handling missing data

Where data are found to be missing the author of the relevant study will be contacted in an

attempt to recover these missing data.

2.9 Data analysis

Data analysis is a generic term that embraces three basic categories: description, analysis

and interpretation (Wolcott, 1994).

28

Mixed method review analysis involves two methods of synthesis: first synthesis focusing on

quantitative methods to measure the effects of the contextual enhancers as therapeutic

methods and second synthesis focusing on qualitative studies exploring the experiences of

patients (How & Why? Questions). The segregated approach adopted by JBI maintains a

clear distinction between quantitative and qualitative evidence and requires individual

syntheses to be conducted prior to the final “mixed-method” synthesis (JBI Manual review,

2011).

2.9.1 Qualitative Data Analysis

The aim of the qualitative research analysis is to develop concepts which will help us to

understand the contextual enhancers in natural settings, giving due emphasis to the

meanings, experiences, and view of the patients and practitioners (Pope and Mays, 1995).

Approaches to analysing qualitative data

There are two approaches to analysing qualitative data: the deductive approach and the

inductive approach (Spencer et al., 2004).

(i) The deductive "top-down" approach involves using a structure or predetermined

framework to analyse data, whereby the researcher imposes their own structure or theories

on the data and then uses these to analyse the transcripts (Williams et al., 2004). This

approach is relatively quick and easy, but it is inflexible and can potentially bias the whole

analysis process as the coding framework has been decided in advance, which can severely

limit theme and theory development. This approach is useful in studies where researchers

are already aware of the probable study concepts (Williams et al., 2004).

(ii)The inductive “bottom-up” approach (the most common approach used in practice)

involves analysing data with little or no predetermined theory, structure or framework and

uses the actual data to derive the structure of analysis. This approach is comprehensive and

therefore time-consuming and is most suitable where little or nothing is known about the

study concepts (Lathlean, 2006).

Methods of analysing qualitative data

(i) Meta-ethnography (interpretive synthesis)

This is concerned with development of new concepts and generating new theoretical

knowledge related to the subject of interest and does not seek to aggregate the data but to

interpret the data to generate new theory. The outputs of a meta-ethnographic review do

not bring together the existing research as much as they generate new findings that extend

the theoretical assumptions of the primary research. The interpretations and explanations

in the original studies are treated as data and are translated across several studies to

produce a synthesis with emphasis on preservation of meaning of the original studies (JBI

manual review, 2011).

29

(ii) Textual Narrative Synthesis

This is useful in drawing together different types of research evidence (e.g. qualitative and

quantitative); it is simple narrative description of the extracted articles (JBI manual review,

2011).

(iii) Thematic content analysis

This process involves analysing transcripts, identifying themes within those data and

gathering similar themes together to form concepts. It is useful in drawing conclusions

based on common elements across otherwise heterogeneous studies (JBI manual review,

2011).

(iv) Meta-aggregation (integrative synthesis)

With respect to summarizing data, the reviewer avoids re-interpretation of included studies,

but instead accurately and reliably presents the findings of the included studies as intended

by the original authors. This process aggregates findings into a combined whole that is more

than the sum of the individual findings in a way that is analogous to meta-analysis. Meta-

aggregation involves assembling the findings of studies and pooling the findings through

further aggregation based on similarity in meaning (Pearson, 2004).

The JBI model of qualitative data synthesis uses a meta-aggregative method because it is

sensitive to the nature and traditions of qualitative research and sensitive to the practicality

and usability of the primary author’s findings and does not seek to re-interpret those

findings, unlike some other methods of qualitative synthesis. A strong feature of meta-

aggregation is that it seeks to enable generalizable statements in the form of practical

clinical recommendations to guide practitioners and policy makers (Hannes and Lockwood,

2011).

Data synthesis in a meta-aggregative review requires a three-step process:

1 Extraction of all findings from all included papers with an accompanying illustration and

establishing a level of credibility for each finding through a consensus process between two

reviewers. The extracted findings are loaded into tables according to PICO, with a table for

setting, table for populations, table for interventions, table for comparators and table for

outcomes.

2 Coding the data systematically by identifying key patterns, followed by category

generation based on similarity in wording, or concepts.

3 Structuring the categories into four or five themes which are then analysed (synthesized)

in combination to develop theoretical constructs, seeking alternative explanations of the

data until meaningful conclusions are reached (Bradley et al., 2007).

30

The JBI-QARI computer software was developed specifically to facilitate the process of

meta-aggregation for qualitative research.

Table 2.9.1, comparing different methods of qualitative data analysis

Methods Thematic analysis Meta-aggregation Meta-ethnography

Purpose Aggregate findings of 2 or more studies

Aggregate the findings of included studies

Generate new theory use processes of interpretation

Evidence of Interest

Qualitative research studies findings

Qualitative research studies findings

Qualitative research studies findings

Search Strategy

Not comprehensive or exhaustive; seeks saturation – theoretical sampling

Comprehensive; detailed search strategy at protocol stage required

Not comprehensive or exhaustive; seeks saturation – theoretical sampling

Critical Appraisal

Not specified Required, using standardized critical appraisal instrument

All studies included as each may provide insight into the phenomena of interest

Data Extraction

Extraction of major/recurrent themes in literature

Extraction of findings PLUS data that gives rise to finding using data extraction instrument

Extraction of key concepts

Method of Synthesis

Aggregation of themes/ metaphors/ categories

Aggregation of findings into categories; and of categories into synthesized findings

refutational synthesis Reciprocal translation; Line of argument synthesis

Outcome A summary of findings of primary studies under thematic headings

Synthesized findings that inform practice or policy in the form of a standardized chart

Higher order interpretation of study findings

Software Available

NO (Although QARI can be used)

Yes NO (Although QARI can be used)

Dimensions of Qualitative data analysis

Qualitative data have three dimensions: (i) the context (e.g. bedside, out-patient

department, etc); (ii) the people (e.g. patients’ experience and expectation); and (iii) the

interactions (e.g. how the patient reacts with the practitioner).

Inductive approaches using Meta-aggregation and thematic content analysis will be used in

the qualitative data analysis because firstly, it was the approach approved by the JBI,

secondly, this approach allow combination of both qualatitive and quantative data to

generate conclusions without predetermined concepts and thirdly it maintain the findings of

the included studies as intended by the original authors.

31

Qualitative research findings will be pooled using JBI-QARI where textual pooling is not

possible the findings will be presented in narrative form.

2.9.2 Quantitative data analysis

This will involve collection, combination and summarization of the results from the selected

quantitative studies in this review. Data synthesis will involve statistical synthesis (meta-

analysis) and narrative synthesis (Higgins et al., 2011).

Review manager software (RevMan) will be used for data entry and analysis. The data will

be analysed for strength of evidence and whether the observed effects are consistent across

studies, exploring the relationships in the data to find reasons for any inconsistencies and to

draw reliable conclusions (Deeks et al., 2001).

Descriptive statistics will be utilized to summarize the data, using measures of central

tendency such as the mean, median and mode, or measures of variability such as range and

standard deviation, graphical description of data through graphs and charts, tabulated

description (Cross-tabulation) for comparative analysis, which can be categorized into rows

and columns to create two or three way tables (Scott et al., 2003; Hartas, 2015).

2.10 Meta-analysis

Meta-analysis is a statistical technique used to summarize quantitative data from several

studies into a single estimate of the effect (effect size) (Deeks et al., 2006). Any standardized

index can be an “effect size” (e.g., standardized mean difference, correlation coefficient and

odds-ratio), but must be comparable across studies (standardization) represent magnitude

& direction of the relationship and be independent of sample size.

The effect size for the categorical variables are expressed as an odds ratio (OR) or risk ratio

(RR) (called also relative risk) while the effect size for the continuous variables are expressed

as the mean difference (MD); and the standardized mean difference (SMD) (Deeks et al.,

2006). The standardized mean-difference effect size (SMD) can be computed from means

and SD using t-test and a one-way ANOVA, then the weighted mean differences (WMD) and

their 95% confidence intervals can be calculated for analysis (Deeks et al., 2006).

The concept of studies weighting reflects the value of the evidence of any particular study

and each studies are weighted according to the inverse of their variance such that larger

studies tend to contribute more than smaller studies to the weighted average.

Consequently, when studies within a meta-analysis are dominated by a very large study, the

findings from smaller studies are practically ignored (Higgins et al., 2011).

2.10.1 Assessment of heterogeneity

Heterogeneity in meta-analysis refers to the variation in study outcomes between studies

which can be clinical heterogeneity among the participants and outcomes and

32

methodological heterogeneity in study design, risk of bias, attrition, etc. (Higgins et al.,

2003). Heterogeneity will be tested using the Q statistic. Cochrane's Q statistic is calculated

as the weighted sum of squared differences between individual study effects and the pooled

effect across studies, with the weights being those used in the pooling method (Cooper et

al., 2009).

P values will be obtained by comparing the statistic with a chi-square test distribution with k

−1 degrees of freedom (where k is the number of studies). A P value of <0.10 will be

adopted since the Q statistic tends to suffer from low differential power. The test will be

considered significant if the overall score is P < 0.05 (Cooper et al., 2009).

The consistency of therapy outcomes across studies will be evaluated using the I² statistic.

The I² statistic describes the percentage of variation across studies that is due to

heterogeneity rather than chance (Higgins and Thompson, 2002; Higgins et al., 2003). I² =

100% x (Q-df)/Q. I² is an intuitive and simple expression of the inconsistency of studies’

results. A value of I² ≤50% represents low heterogeneity, 50–75% moderate, while ≥75%

represents high heterogeneity (Higgins & Thompson, 2002). The 95% confidence interval

will be calculated for each I² value. The statistic I² measures the extent of inconsistency

among the studies’ results, interpreted as approximately the proportion of total variation in

trial estimates that is due to heterogeneity rather than sampling error (Higgins et al., 2003).

Fixed-effects or a random-effects model

A fixed-effects model is based on the assumption that the sole source of variation in observed outcomes is that occurring within the study; that is all studies considered to have been conducted under similar conditions with similar subjects and the effect expected from each study is the same. Consequently, it is assumed that the models are homogeneous; there are no differences in the underlying study population, no differences in subject selection criteria, and treatments are applied the same way (Ades and Higgins, 2005).

If there is very little variation between trials, then I² will be low and a fixed effects model might be appropriate. An alternative approach, 'random effects', allows the study outcomes to vary in a normal distribution between studies. Many investigators consider the random effects approach to be a more natural choice than fixed effects, for example in medical decision making contexts (Ades and Higgins, 2005).

Fixed-effects models will be used to further analyse in this research and the Heterogeneity

will be further explored by conducting subgroup analyses. For comparative purposes both

fixed effect and random effects outcomes will be reported (Higgins et al., 2003).

Potential publication bias will be assessed through funnel plots. Funnel plots provide scatter

plots of the treatment effects of the selected studies against a measure of each study's

sample size. In the absence of bias, the plot should resemble an inverted symmetrical

funnel.

33

2.10.2 Subgroup analysis

Subgroup analysis is a form of analysis used to evaluate studies with common PICO

characteristics. It evaluates the strength of common characteristics in the meta-analysis

results. For example, subgroup analysis can be performed using studies employing similar

contextual enhancers. Other factors affecting the outcome variables could be used for

future subgroup analyses (Egger et al., 2008).

2.10.3 Sensitivity analysis

Sensitivity analysis is a form of analysis used to evaluate the differences between the overall

outcomes and outcomes from studies with low risk of bias through excluding studies with

high risk of bias. It will be used to evaluate the robustness of the meta-analysis results

(Egger et al., 2008).

2.11 Narrative synthesis

Where statistical pooling is not possible the findings will be presented in narrative form

including words, text, tables and figures to aid in data presentation where appropriate, used

to summarize and explain the findings of the selected studies

2.12 Software for qualitative and quantitative data analysis

Special computer software will be used to enhance the qualitative analyses by: creating,

applying, and refining categories; tracing linkages between concepts; and making

comparisons between cases and events. NVivo, the most popular qualitative data analysis

package, can speed up the analysis process and make it easier for researchers to experiment

with different codes, test different hypotheses about relationships, and facilitate diagrams

of emerging theories and preparation of research reports (Coffey & Atkinson, 1996; Richards

& Richards, 1994). Statistical analyses of quantitative data can be carried out using

StatsDirect and Stata.

34

Future plan to Test CEP acceptability and credibility (Post PhD plan)

2.13 Methodology for study to test CEP acceptability

Aim

Test CEP acceptability and credibility

Objectives and research design

Mixed experimental study comprising collecting quantitative data using survey (n=100) GPs

to explore the GPs overviews about acceptability of the CEP and measure their responses

followed by an in-depth interview with (n=5) GPs selected randomly from those who

completed the survey to explore their views about the best way to use the CEP in clinical

practice.

Strategy for the survey

The survey questionnaire design will incorporate the following features: it will be short, self-

contained and self-explanatory, using a personalised covering letter, coloured ink and

stamped return envelopes; the participants will be contacted before and after sending the

questionnaires and another copy of the questionnaire will be sent to non-respondents.

The study population: 100 randomly selected GPs in Nottingham

Quantitative data collection: postal questionnaires will be sent with an information pack

and stamped return envelopes to the GPs using pre-paid envelopes. Follow up contact will

be made after three weeks and non-respondents will be sent a second copy of the

questionnaire.

Strategy for the interview 30 minutes’ interview for five selected GPs from those who

completed the survey.

Data analysis

The qualitative and quantitative data will be analysed separately, after that combined

analysis will be conducted to evaluate the acceptability and credibility of the CEP.

35

Chapter 3 Results

3.1 Delphi results

Twenty world-renowned experts in placebo research and contextual enhancers were invited

to participate in the Delphi process via e-mail of which 75% (15 out of 20) accepted the

invitation and responded to the first round questionnaire. The panel members comprised a

mix of different specialities: two rheumatologists; two orthopaedic surgeons; two general

practitioners; two scientists; two general medicine specialists; two patients; one

neurologist; one university lecturer and methodologist; and one nurse. Five countries were

represented, specifically the UK, Italy, Denmark, Australia, USA and China (see the names of

the panel members in Appendix 5).

The responses to the first questionnaire produced a total of 56 factors: 15 practitioner

factors; 11 patient factors; 7 practitioner-patient interaction related factors; 8

environmental factors; and 8 other factors. These factors were sent to the panel members

for ranking, see appendix (4).

87% (13 out of 15) of the panel members completed the second round ranking. Contextual

enhancers with mean ranking scores of 4 or more were accepted (n=16) and contextual

enhancers with mean ranking scores of less than 4 were rejected (n=8). The voted ranking

mean was variable depending on the importance of the contextual enhancers and was high

(9.15) for practitioner’s empathy and low (4.76) for environmental factors, see Table 3.1.

The 95% Confidence Interval was narrow for all responses, with standard deviation (SD)

between 0.5 and 3, which indicates that if we were to ask the same question of a different

sample, we would be most likely to get a similar result.

The 16 final contextual enhancers are: six practitioner factors (practitioner’s empathy,

Practitioner’s confidence, Practitioner’s communication skills, Practitioner’s experience and

knowledge, Professionalism, and Practitioner beliefs/illness perceptions); three patient

factors (Patient active involvement, Patient beliefs/illness perception and Patient

expectation & experience); two practitioner-patient relation factors (Holistic assessment and

Practitioner – patient interaction); and five other factors (Treatment characteristics,

Information about the disease and management options, Duration of consultation, Regular

follow-up and Environmental factors) (see Table 3.1).

It was difficult to analyse the responses according to the speciality of the respondent

because the Delphi process was carried out with complete anonymity and confidentiality.

36

Table 3.1 Contextual elements included (mean score > 4)

Contextual elements Number

of voters

Mean

score

95%

Confidence

Interval

Empathetic 13 9.15 8.61 - 9.69

Patient active involvement 13 7.76 6.99 – 8.53

Duration of consultation 12 7.66 6.64 – 8.68

Patient beliefs/illness perception 13 7.30 6.18 – 8.42

Practitioner’s Communication skills 38 7.05 6.36 - 7.72

Treatment characteristics 13 6.76 4.71 - 6.08

Information about the disease and management options 13 6.69 5.53 - 7.85

Practitioner – patient interaction 12 6.58 5.44 – 7.72

Practitioner confidence 13 6.38 5.22 - 7.54

Holistic assessment 25 6.07 5.24 - 6.92

Practitioner experience and knowledge 39 6.04 5.28 - 6.81

Professionalism 51 6.03 5.27 - 7.55

Practitioner beliefs/illness perceptions 13 5.76 4.22 - 7.3

Regular follow-up 12 5.75 4.48 – 7.02

Patient expectation & experience 102 5.54 5.05 - 6.04

Environment 78 4.76 4.19 - 5.33

Table 3.2 Contextual elements excluded (mean score ≤4)

Contextual elements Numbers

of voters

Mean

s

95%

Confidence

Interval

Doctor’s availability when needed 12 3.91 2.57 – 5.25

Practitioner’s gender, age and ethnicity 13 3.69 2.35 - 5.03

37

Cost of treatment 13 3.61 2.1 – 5.12

Waiting area 13 3.53 2.45 – 4.61

Patient’s gender, age and ethnicity 13 3.23 2.26 – 4.2

The practitioner organizes routine communication

meetings among doctors and patients with same disease

12 3.00 1.53 – 4.47

Access to practitioner performance data for patient 12 2.41 1.35 – 3.47

The practitioner having a stethoscope around his/her

neck

12 1.25 0.38 – 2.12

Table 3.3 Amalgamated contextual elements that share similar meaning

Contextual

elements

Amalgamated from

Communication Verbal + Non-verbal communication + appropriate use of Touch

Professionalism Warm and friendly + Practitioner being genuine and honest + Practitioner

appearance + addressing patients with reduced capacity

Practitioner

experience and

knowledge

Experience and Knowledge + practitioner’s knowledge of patient history +

Practitioner seniority

Patient

expectation &

experience

Patient expectation + patient experience of illness and experience of

treatment + Anxiety about condition/treatment + Prior experience in

health-care environments + Suggesting support groups, where

appropriate, e.g. Crohn’s & Colitis UK, Arthritis UK + Research trial

incentives

Practitioner-

patient interaction

Established relationship, Connecting + Congruence on problem + Social

interaction with other patients

Holistic

assessment

Holistic assessment+ Thorough examination of relevant part of body

Environment Room conditions + Access + Equipment + Sound/noise levels

Treatment

characteristics

Presentation of treatment + Novelty of treatment + Side effects of

treatment + Mode and methods of administration + Treatment

38

characteristics and How treatment is described

3.2 The outcomes of four contextual enhancers searched using 4 databases

The outcomes of the contextual enhancer search are shown in Table 3.2; each factor was

searched separately then the citations were exported electronically to the Endnotes. A total

of 2670 citations were found from searching four contextual enhancers. 1110 of the

duplicated citations (articles) were detected and removed using Endnotes. The remaining

articles were stored in the Endnotes for future addition to the next search results.

Table 3.2: outcomes of four contextual enhancers search

Contextual enhancers searched separately

Citation with each database searched

Medline PsycINFO EMBASE CINAHL

1 Empathy 195 148 264 298

2 Practitioner-patient relation/interaction

188 134 138 596

3 Patient active involvement 33 18 62 178

4 Duration of the consultation 41 130 7 66

Total citation 2670

Duplicate reference 1110

Trash 587 (some citations are repeated 3 time or 4 times but sent to trash as one article)

Remaining articles 2083

3.3 Example of search related to contextual enhancer (Empathy or empathetic)

Database searched

Ovid MEDLINE(R) 1946 to Present

Search criteria Adult 19 and plus, Human, 1946 to Present

Contextual enhancers

Empathy or empathetic

Search Terms Practitioner or Physician or Nurses or nurse practitioners

Patient Empathy or empathetic

Number of citations

47231

1130293 5191

Boolean operator

(47231) and (1130293) and (5191) = Number of final citations (195)

39

Database searched

PsycINFO 1806 to June Week 1 2016

Search criteria Adult 19 and plus, Human, 1806 to June Week 1 2016

Contextual enhancers

Empathy or empathetic

Search Terms Practitioner or Physician or Nurses or nurse practitioners

Patient Empathy or empathetic

Number of citations

39167 151078 4962

Boolean operator

(39167) and (151078) and (4962) = Number of final citations (148)

Database searched

EMBASE, 1806 to June Week 1 2016

Search criteria Adult 19 and plus, Human, 1806 to June Week 1 2016

Contextual enhancers

Empathy or empathetic

Search Terms Practitioner or Physician or Nurses or nurse practitioners

Patient Empathy or empathetic

Number of citations

77342

1423528 5401

Boolean operator

(77342) and (1423528) and (5401) = Number of final citations 264

Database searched

CINAHL, 1981 to present

Search criteria Adult 19 and plus, Human, 1981 to present

Contextual enhancers

Empathy or empathetic

Search Terms Practitioner or Physician or Nurses or nurse practitioners

Patient Empathy or empathetic

Number of citations

92410 639984 4016

Boolean operator

(92410) and (639984) and (4016) = Number of final citations (298)

40

Chapter 4 Plan

The main goal of this work was to conduct a comprehensive systematic review including

both qualitative and quantitative methods and meta-analysis to identify the key contextual

enhancers which have therapeutic outcomes in chronic painful conditions, see Gantt chart

appendix -7.

4.1 Plan for the first year, see Gantt chart appendix – 7

[i] Conduct Delphi process to collect consensus about the important contextual enhancers

[ii] Use the terms identified by the Delphi process to search the four major databases

separately, export all the identified citations into the reference manager “Endnotes”,

remove the duplicated articles and then review the abstract of the remaining articles,

removing any articles that do not match the inclusion and exclusion criteria.

[iii] Classify the remaining articles according to the type of study as either qualitative (e.g.

observation, interviews, reports, etc.) or quantitative (e.g. experimental, observational,

survey, etc.) studies.

[iii] Attend relevant courses

4.2 Plan for the second year, see Gantt chart appendix -7

[i] The qualitative studies will be analysed separately. The extracted information will be read

thoroughly to identify key patterns, followed by category generation and then structuring of

the categories into themes, and similar themes will be grouped together to form contextual

enhancers.

[ii] The quantitative studies also will be analysed separately, involving both statistical

synthesis (meta-analysis) and narrative synthesis, all studies will be subjected to quality

assessment.

[iii] Attend relevant courses

4.3 Plan for the final year

[i] Conduct second Delphi process

- To generate several key contextual enhancers that have evidence for therapeutic effect

and that can be packed together to delivered in clinical practice to enhance the treatment

effect.

- Produce simple contextual enhancers package (CEP) (small number < 10 contextual

enhancers)

41

[ii] Write up the final PhD thesis

[iii] Attend relevant courses

4.4 Plan for the future {post PhD}

[i] CEP and training: manual, courses (both face to face and online)

[ii] Feasibility study for CEP through survey and interview sample of GPs to test acceptability

of CEP.

[iii] RCT for CEP to evaluate the treatment effect of CET on its own and together with a

specific treatment.

42

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Dis, 67 (2008), pp. 1716–1723

49

Chapter 5 appendices

Appendix - 1 - PRISMA 2009 Flow Diagram

Records identified through

database searching (n = )

Scre

en

ing

Incl

ud

ed

Elig

ibili

ty

Iden

tifi

cati

on

Additional records identified through other

sources (n = )

Records after duplicates removed

(n = )

Records screened

(n = )

Records excluded

(n = )

Full-text articles assessed

for eligibility

(n = )

Full-text articles excluded,

with reasons

(n = )

Studies included in

qualitative synthesis

(n = )

Studies included in

quantitative synthesis

(meta-analysis)

(n = )

50

Appendix - 2 - Delphi invitation letter

Dear ………….,

Re: A Delphi consensuses for the key contextual factors that may be used to enhance treatment

effect

Invited Panel members: Chris Dowrick, Christian Mallen, Claire Diver, Fabrizio Bennedetti, Ian Harris,

Irving Kirsch, Jianhao Lin, Jonas Bloch Thorlund, Louise Sandal, Malcolm Coy, Michael Doherty, Paul

Dieppe, Stefan Lohmander, Stevie Vanhegan, Wendy Jenkins.

I am a PhD student at Nottingham University and my research project includes a Delphi consensus

approach to generate the key contextual factors that may be used to enhance the treatment effect.

Research evidence around these key contextual factors will be systematically reviewed and a

contextual enhancement package will be developed. My supervisors are Weiya Zhang, Michael

Doherty and Claire Diver.

Considering your expertise in this area, I would be very grateful if you could participate in the Delphi

consensus. Once you agree to participate, you will receive an email with a questionnaire asking you

to suggest key factors that you think are most influential in influencing contextual response. You

will be asked to email these contextual factors to me (not to other panel members to keep the

Delphi anonymity). The list of amalgamated contextual factors will then be sent back to you for

voting/scoring. The consensus will be reached if a contextual factor has gained majority votes or

achieve the predefined threshold. Several rounds of Delphi may be required and a summary of

statistics will be given to assist your voting/scoring for each Delphi round.

As this is the first part of my PhD project, your input would be greatly valued and your name will be

included as co-author for any future publication resulting from this Delphi exercise unless you

choose not to be included.

If you think we have missed anyone from the panel list who could make an important contribution to

this exercise, please let us know their name and email so we can invite them as well. Many thanks in

advance for your help.

Yours sincerely

Dr Ramadan Musa

PhD student

The University of Nottingham

Clinical Sciences Building

Nottingham City Hospital, Nottingham NG5 1PB

Telephone: +44 (0) 115 82 31756

51

Appendix - 3 - The Delphi questionnaire

We are very interested in the contextual factors that can be modified in clinical practice to enhance the

treatment effect. We would therefore like to ask for your personal opinions on which factors (in addition to

the treatment) you think are important and which might be modified in every patient encounter to enhance

the treatment effect. We have classified them into 5 domains, each with possible examples that may be

included. However, please feel free to nominate as many as you wish.

Contextual factors {Defined as the factors related to the overall treatment effect that are not due to the specific/active ingredient of the treatment}

1 Practitioner characteristics (e.g. patient confidence in experience/knowledge of practitioner)

2 Patient characteristics (e.g. expectation of treatment benefit)

3 Patient-practitioner interaction (e.g. positive empathy)

4 Treatment characteristics (e.g. new versus old treatment)

5 Environment (e.g. location - home/surgery/hospital)

6 Please feel free to add any other domains/factors that you think are important

Please return your questionnaire to Dr Ramadan Musa at drrmusa@gmail.com only, to keep your voting

anonymized to other members of the expert panel.

52

Appendix - 4 – The responses of the Delphi panel members

Practitioner factors

1 Empathetic inducing trust and hope in his/her patients, Personality traits: Empathy, authority, sympathy, commitment

13

2 Non-verbal Communication, Listening, Good eye contact, active listening, does not talk down to the patient, the performance of appropriate rituals (e.g. hand washing, eye contact, touching), Good eye contact and the occasional smile, listening, smiling, making eye contact, engaging in active listening, using facial expression, excusing any change of focus.

9

3 Polite attitude – appropriate introduction (hand-shake), Warmth, compassion, interest, patience, Open and friendly, Full attention focused on patient, Focused attention on the other person, handshake, standing to receive and standing when patient leaves, using patient’s name; Forms of address to patient: showing respect and courtesy; being polite, warmth, accessibility

9

4 Knowledge and Experience, Willingness to seek advice from colleagues, Competence, prior experience with treatment

8

5 Knows the treatment history of his/her patients pretty well, including all successes and failures. Same hometown as the patient’s, Pre-existing trust, demonstrates understanding of the problem, Pre-existing patient knowledge, Knowledge of the patient they are about to see, Basic history of treatment journey past to present day. Having read patient’s notes beforehand, Previous experience with practitioner

8

6 Verbal Communication and Language and Vocabulary used, Linguistic and cultural balance, Open questions, Good communication skills, Good adjustable communication style, Humour, Asking, not telling, Quality of dialogue (listening, allowing time for thinking/reflecting, paraphrasing)

8

7 Gender, age and ethnicity 5

8 Smart Dress/appearance, well presented, practitioner not looking tired/ill/tense, Appearance: Clothing and hospital white robe

5

9 Confidence, confidence in treatment 3

10 Job title of practitioner, Formal role, e.g. senior GP, consultant, trainee, etc. 2

11 Practitioner beliefs about cause of given condition, Clinician belief in benefit of treatment 2

12 Being genuine and honest with the other person 2

13 Hygiene 1

14 If the patient is a child or an adult with reduced capacity, I would expect the practitioner to address them as any other patient

1

15 Artefacts (the practitioner, for instance, having a stethoscope around his/her neck) 1

Patient factors

1 Past experience of condition, positive experience, Previous experience with treatment 10

2 Expectation of treatment benefit, Illness perceptions, Positive outcome expectation 10

3 Choice/shared decision making, ability to discuss treatment options and ask questions (doctor-centred, patient-centred, shared decision-making, etc.), patients should play an active part in the treatment and should take part in all the decisions. Active role in treatment, Patient centred approach, understands their role in the treatment plan, Importance of active participation of patient, displaying a balanced attitude to ‘alternative’ treatments suggested by the patient, the practitioner to allow the patient to save face and to acknowledge all their attempts at self-care

9

4 Patient’s belief in treatment and adherence to treatment, openness to unexpected benefits, Patient belief in treatment, Good understanding of potential result of treatment, something that both parties can believe in, something that both parties think is powerful, Patient confidence in experience of the practitioner, Conditioned responses (routines in treatment,

8

53

expectations towards treatments or behaviour).

5 Patient open-minded, optimistic. Outgoing, Openness to different approaches, the desire to get better, Being ready for change, Personality traits: trust, acceptance, Personal traits – open minded vs. reluctant

7

6 Social status of patient, Socio-economic position, with very low level education, but obeys doctor’s suggestions, Get enough social support, Education, Awareness of social dimension, culture

7

7 The patient’s needs should be assessed before starting any treatment, adjust his/her behaviours and attitudes to the patient’s needs. Carefully examines the patients’ needs before any close interaction with them, taking along notes of questions to ask and making notes of what is said, tailored to the perceived need and wish of the patient, the practitioner to be caring and comforting, patient to be ministered to, for what they say to be acknowledged by practitioner and understood

6

8 Anxiety about condition/treatment, Anticipatory anxiety about the possible painful procedure should be avoided, Symptom severity, Type of presenting condition, Nature of disease (common cold vs. terminal cancer), Severity of disease (level of disability/pain)

5

9 Gender, age and ethnicity 5

10 Explanation of condition and management options, the practitioner must explain the treatment in detail, with particular regard to the expected beneficial effect, they require a detailed explanation of the treatment, including duration, possible alternatives, drug dose, etc., Information on condition, realistic prognosis discussion

4

11 Established relationship, connecting – achieving that moment of true connection with another person, Collaboration, Mutual trust, Partnership building between patient and HCP

4

Patient-practitioner encounter factors

1 Duration of consultation, Unhurried interview/assessment, not being rushed out at the end of the consultation, i.e. enough time allowed for patient, Amount of time for the consultation, the amount of time for an encounter (to talk, build trust) could also be important

7

2 Use of touch, appropriate positive touch during examination, Use of touch 5

3 Thorough examination of relevant part of body, uses ‘hands on’ clinical examination 3

4 Holistic care 1

5 interest in the patient 1

6 Feeling listened to 1

7 Congruence on problem formulation and management plan 1

Treatment factors

1 Mode and methods of administration e.g. exercise vs passive treatments, e.g. medication, Passive or active treatment (taking pill vs. exercise), Technical vs. non-technical

9

2 Explain treatment characteristics, Apparent scientific rationale for treatment, How treatment is described – positive vs neutral, Proposed journey of treatment & time line, Proposed future changes to treatment, treatment plan will help, Offer of written instructions/details of treatment/discussion, Being told that if the first treatment fails, then there are others that can be tried, Information on condition, realistic prognosis, treatments available (including doing nothing) with benefits and harms discussion, Education of patient to explain reasons for treatment changes, Explanation of practitioners thinking/reasoning, Keeping patients fully informed, The way a treatment is phrased – for instance, who wants conservative treatment? Sounds like something that does not work

9

3 Novelty of treatment 7

4 Presentation of treatment – colour, size, packaging and Number of medications, appearance of treatment (colour, size of pills)

5

5 Side effects of treatment, Possible side effects should be described, fully understands side 3

54

effects if there are any

6 Frequency/duration of treatment 3

7 cost 2

Environment

1 Room clean vs unclean, Open, light, positive environment versus cramped, dark negative environment, Welcoming room, Familiar room, Uncluttered environment, Heated or ventilated depending of time of year, Comfortable, Capacity for additional person to attend (wife, carer), Consider refreshments (hot or cold), feels safe for both practitioner and patient, and allows them both to relax, Medium sized room with window, sterile/clinical, comfortable, Lighting level, Smell/odour

9

2 Location: primary or secondary care; health or non-health setting; private vs NHS setting, one stop shop, Indoor/outdoor

8

3 Transport and Access to treatment site, Community clinics easy to reach, Good access for public transport/medilink buses/parking, Provision for specific needs, i.e. access, Way finding

5

4 Seating arrangements – congruence of chairs, relative positions vis a vis desk, Formality vs informality of setting, Provision of privacy and safety, Amount of other people/privacy

4

5 New vs old equipment, Prominence of computer in consulting room, Avoidance of inappropriate computers, telephones, ‘big boys’ toys’, etc., Acknowledge that appearance and site of therapeutic equipment may be daunting

4

6 Sound/noise levels, No distractions, Noise 3

7 Waiting room with range of chair sizes, Space to sit down 2

8 Prior experience in health-care environments, Expectation towards environment, Appropriate and inappropriate objects/factors within environments (mirrors, windows, screens or enclosures, views to specific sceneries)

1

Other factors

1 Research trial Incentives (e.g. financial, access to care) for taking treatment, Is the treatment part of a bigger study? Opportunity to take part in a research project, Blinding of patient or practitioner (if in trials)

4

2 Continuity of care, Further appointment, The practitioner regularly follows up, but not too often

3

3 They request the doctor’s availability when needed (e.g. mobile phone number), Patients have doctor’s phone number

2

4 Social interaction with other patients who are suffering or who have experienced a failure in their treatment could induce negative expectations which in turn may lead to clinical worsening, Tendency to rely on “others’” stories about treatment effect

2

5 The practitioner organizes routine communication meetings among doctors and patients with same disease

1

6 Access to practitioner performance data for patient 1

7 Suggesting support groups, where appropriate, e.g. Crohn’s & Colitis UK, Arthritis UK 1

8 Offer of recording the consultation 1

55

Appendix - 5 - statistical analysis of all the Delphi responses

Practitioner factors

Practitioner related Contextual enhancers

Number of voters

Mean score (x̄)

Standard deviation (SD)

95% Confidence Interval (CI)

Range

1 Empathetic 13 9.15 0.98 8.61 - 9.69 8.62 to 9.69

2 Warm and friendly 13 8.07 1.65 7.17 - 8.97 7.18 to 8.98

3 Verbal Communication 13 7.92 1.49 7.11 - 8.73 7.11 to 8.74

4 Non-verbal Communication 13 7.61 1.89 6.58 - 8.64 6.59 to 8.65

5 Knowledge and Experience 13 7.07 1.89 6.04 - 8.1 6.05 to 8.11

6 Knows patient history 13 6.92 1.75 5.97 - 7.87 5.97 to 7.88

7 Holistic assessment 13 6.84 1.90 5.8 - 7.88 5.81 to 7.88

8 Explanation of condition and management options

13 6.69 2.13 5.53 - 7.85 5.53 to 7.85

9 Practitioner confidence 13 6.38 2.14 5.22 - 7.54 5.22 to 7.55

10 Practitioner being genuine and honest

13 6.07 2.87 4.51 - 7.63 4.52 to 7.64

11 Practitioner beliefs/illness perceptions

13 5.76 2.83 4.22 - 7.3 4.23 to 7.31

12 Practitioner appearance 13 5.61 2.06 4.49 - 6.73 4.49 to 6.74

13 Practitioner seniority 13 4.15 2.51 2.78 - 5.52 2.79 to 5.52

14 Gender, age and ethnicity 13 3.69 2.46 2.35 - 5.03 2.35 to 5.03

Patient factors

Patient related Contextual enhancers

Number of voters

Mean score (x̄)

Standard deviation (SD)

95% Confidence Interval (CI)

Range

1 Patient expectation 13 8.07 2.01 6.97 – 9.17 6.98 to 9.17

2 Patient active involvement 13 7.76 1.42 6.99 – 8.53 7 to 8.54

3 Patient beliefs/illness perception 13 7.30 2.05 6.18 – 8.42 6.19 to 8.43

4 Anxiety about condition/treatment 13 6.30 1.70 5.37 – 7.23 5.38 to 7.23

5 Patient’s personality 13 6.15 1.95 5.09 – 7.21 5.09 to 7.21

6 Patient experience 13 6 2.88 4.43 – 7.57 4.43 to 7.57

7 Social status of patient 13 4.53 2.22 3.32 – 5.74 3.33 to 5.75

8 Gender, age and ethnicity 13 3.23 1.78 2.26 – 4.2 2.26 to 4.2

Treatment factors

Treatment related Contextual enhancers

Number of voters

Mean (x̄)

Standard deviation

95% Confidence Interval (CI)

Range

1 Treatment characteristics and how treatment is described

13 6.76 2.68 5.3 – 8.22 5.31 to 8.23

2 Mode and methods of administration

13 5.84 3.18 4.11 - 7.57 4.12 to 7.58

3 Side effects of treatment 13 5.23 2.42 3.91 – 6.55 3.91 to 6.55

4 Novelty of treatment 13 4.76 2.55 3.37 – 6.15 3.38 to 6.16

5 Presentation of treatment 13 4.38 2.959 2.77 – 5.99 2.78 to 5.99

6 Cost of treatment 13 3.61 2.78 2.1 – 5.12 2.1 to 5.13

56

Environmental factors

Environment related Contextual enhancers

Number of voters

Mean score (x̄)

Standard deviation (SD)

95% Confidence Interval (CI)

Range

1 Room conditions 13 6.07 3.01 4.43 – 7.71 4.44 to 7.71

2 Location 13 5.23 2.94 3.63 – 6.83 3.63 to 6.83

3 Transport and Access to treatment site

13 5.07 2.49 3.71 – 6.43 3.72 to 6.44

8 Prior experience in health-care environments

13 4.61 2.32 3.34 – 5.88 3.35 to 5.88

5 Equipment 13 4.38 2.21 3.17 – 5.59 3.18 to 5.59

6 Sound/noise levels 13 4.30 2.35 3.02 – 5.58 3.03 to 5.59

7 Waiting area 13 3.53 1.98 2.45 – 4.61 2.46 to 4.62

Other contextual enhancers

Other Contextual enhancers Number of voters

Mean score (x̄)

Standard deviation (SD)

95% Confidence Interval (CI)

Range

1 Continuity of care, Further appointment 12 5.75 2.34 4.48 – 7.02 4.48 to 7.02

2 Research trial Incentives 12 4.25 1.91 3.21 – 5.29 3.21 to 5.29

3 Suggesting support groups, where appropriate, e.g. Crohn’s & Colitis UK, Arthritis UK

12 4.25 2.92 2.59 – 5.91 2.59 to 5.91

4 If the patient is a child or an adult with reduced capacity, I would expect the practitioner to address them as any other patient

12 4.25 3.04 2.52 – 5.98 2.52 to 5.98

5 Social interaction with other patients 12 4.41 2.27 3.12 – 5.7 3.13 to 5.7

6 They request the doctor’s availability when needed

12 3.91 2.46 2.57 – 5.25 2.58 to 5.26

7 The practitioner organizes routine communication meetings among doctors and patients with same disease

12 3 2.59 1.53 – 4.47 1.53 to 4.47

8 Access to practitioner performance data for patient

12 2.41 1.88 1.35 – 3.47 1.35 to 3.48

9 The practitioner having a stethoscope around his/her neck

12 1.25 1.54 0.38 – 2.12 0.38 to 2.12

57

Appendix - 6 - Table (3.4) Name of the Delphi panel members

Name of Delphi member

Speciality Country

1 Prof Michael Doherty

Head of Department and Director of Clinical & Epidemiological Research, Faculty of Medicine & Health Sciences

Rheumatologist UK

2 Prof Paul Dieppe Professor of health and well-being at Exeter Medical School

Rheumatologist UK

3 Prof Jianhao Lin Professor of Orthopaedic surgery Orthopaedic China

4 Prof Ian Harris Professor of Orthopaedic surgery Orthopaedic Australia

5 Professor Christian Mallen

Professor of General Practice Research

General Practice

6 Prof Chris Dowrick Primary Medical Care General Practice UK

7 Dr Claire Diver Lecturer, Faculty of Medicine & Health Sciences, Nottingham university

Lecturer, Faculty of Medicine

UK

8 Prof Irving Kirsch Associate Director of the Program in Placebo Studies and a lecturer in medicine at the Harvard Medical School

Professor of Medicine

USA

9 Prof Ted Kaptchuk Professor of Medicine at Harvard Medical School, expert in contextual healing

Professor of Medicine

USA

10 Prof. Fabrizio Benedetti

Professor of physiology and neuroscience and placebo expert

Professor of physiology

Italy

11 Prof Jonas Bloch Thorlund

Sports Science and Health Sports Science and Health

Denmark

12 Dr Louise Sandal Sports Science and Clinical Biomechanics

Sports Science and Health

Denmark

13 Mr Malcolm Coy Patient Patient UK

14 Stevie Vanhegan Patient Patient UK

15 Wendy Jenkins Nurse Nurse UK

58

Appendix - 7

Reviw registration

The protocol has been sent to the centre of the Joanna Briggs Institute for registration

Reliability and external validity

Reliability (dependability) in qualitative research is not based on outsiders getting the same results,

but on outsiders concurring that, given the data collected, the results make sense. In other words,

the results are dependable and consistent (Lincoln & Guba, 1985), while in a quantitative study

reliability refers to the extent to which research findings can be replicated.

In relation to a qualitative study, external validity (Generalizability), representativeness or

transferability mean that the study’s findings can apply to other situations. This is difficult to achieve

because “In qualitative studies a single case or small non-random sample is selected precisely

because the researcher wishes to understand the particular in depth, not to find out what is

generally true of the many” (Merriam, 1998, p. 208), while in quantitative studies external validity is

enhanced using a priori conditions.

Potential limitations and weaknesses of the review

Publication bias due to including only published studies.

Language limitations due to including only studies published in English language.

Some articles might contain incomplete data.

Ethical considerations

Ethics approval is not needed for a systematic review or for the Delphi method. The Delphi invitation

letter to each panel member will include written explanation of the Delphi methods and the panel

member’s voluntary response will be regarded as written consent. The participants’ identity will be

known to the other panel members but their opinion and the extracted data will be coded to protect

their privacy and will be stored securely. The study team will maintain neutrality throughout the

study and will be self-reflective upon their role as researchers. This Delphi study will subscribe to the

principles of privacy, confidentiality, mutual respect, and the researchers will follow moral and

ethical principles (Denzin and Lincoln, 1994). A policy of complete honesty and transparency in

dealing with the retrieved articles will be followed. The used information will be attributed

appropriately to the source of the data. Copyright in the transfer of the extracted data will be

maintained.

Dissemination

The review outcomes will be fed back to the University staff and the local hospital staff. The results

will be submitted to medical journals such as the Lancet for publication, to make them available to a

wider audience. In addition I will present a poster at the University’s annual poster conference. I will

submit an abstract of the review to the regional Rheumatology Society meeting for a regional

audience and a copy to the annual meeting of the British Society for Rheumatology.

59

Appendix -8 -Proposed Ganttthe research project

Task Year 15 2016 2017 2018

Months 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3

1 Registration & School Welcome Event

2 Meeting with the supervisors

Every 2 weeks Monthly 2 Monthly 3 Monthly Monthly

3 Conducting Delphi process

4 Formalize the review question & the protocol

5 Scoping review

6 Attending courses

Any time suitable courses become available

7 Initial literature retrieval

8 Reading the articles to collect the information

9 Initial data analysis

10 Writing and submitting first year report

11 Holiday ? ? ? ?

12 Retrieving all available literature

13 Reading the articles to collect the information

14 All data analysis (mixed methods analysis)

14 Writing up the final year report

15 Final draft submission

16 Dissemination

60

Appendix -9 - Table 4.2 Courses attended in the first year

Courses Training Units

Date

1 Systematic review (Medicine and Health Sciences Faculty)

1 02/12/2015

2 Introduction to qualitative research 1 08/2/2016

3 Epidemiological Study Design 1 11/2/2016

4 Getting going on your thesis 1 12/2/2016

5 Pg Diploma of clinical education (two days course) 8th & 9th/3/2016

6 PowerPoint: Creating a Research Poster 1 22/6/2016

7 Introduction to quantitative research 4 27/6/2016

8 Faculty postgraduate Research Forum (Medicine) 4 29/6/2016

9 Finishing your thesis 1 7/7/2016

10 Further qualitative research 2 19/7/2016

Total units

16

Table 4.4 Numbers and dates of the supervisor’s meetings

Number of meeting

Date of supervisor meeting Subject discussed in the meeting

1 1/12/2015 Introduction meeting

2 14/12/2015 Reviewed the research protocol

3 12/1/2016 Reviewed the search term and search strategy

4 26/1/2016 Initiated the Delphi process

5 16/2/2016 Discussed the progress of the Delphi process

6 29/2/2016 Delphi process progress

7 22/3/2016 Delphi process progress

8 26/4/2016 Reviewed the Delphi outcomes and search terms

9 24/05/2016 Formulated the search strategy

10 28/6/2016 Reviewed the first year report and search progress

11 12/7/2016 Discussed the first year report

12 26/07/2016 Discussed the first year report and future studies

61

Glossary

Terms Definition

Empathy Understanding what others are feeling, you have experienced it yourself or can

put yourself in their shoes. "I know it's not easy to lose weight because I have

faced the same problems myself."

Sympathy Acknowledging another person's emotional hardships, "Trying to lose weight can

feel like an uphill battle at first."

Compassion Blending of understanding and acceptance of others, Compassion is simply a

variation of love or sadness, not a distinct emotion

Passion very strong feeling about a person or thing

Nocebo effect is the adverse reaction experienced by a patient who receives placebo therapy

Placebo substance given to someone who is told that it is a particular medicine, either to

make that person feel as if they are getting better or to compare the effect of the

particular medicine when given to others

Professionalism defined as a set of values, behaviours, and relationships, specifically, this includes

integrity, compassion, altruism, continuous improvement, excellence, and

working in partnership with members of the wider healthcare team (Engel,

Dmetrichuk and Shanks, 2009)