Editorial

The case for invasive placebo – is the devil in the detail?

In this issue of Anaesthesia we pub-

lish a paper by Kumar et al. evalu-

ating the effect of pre-operative

stellate ganglion block on postoper-

ative tramadol consumption follow-

ing surgery to fixate upper limb

fracture [1]. This research study

was prompted by the 2011 case ser-

ies from McDonnell et al. that

showed a marked benefit of stellate

ganglion block performed for simi-

lar indications with respect to post-

operative pain scores and analgesic

requirements [2]. Two editorials

accompanied McDonnell et al.’s

paper; one discussed the potential

for modulation of acute somatic

pain by the autonomic nervous sys-

tem [3], and the other called for

robust substantiation of the findings

before such an approach was incor-

porated into routine clinical prac-

tice [4]. Kumar et al. have now

performed a randomised, double-

blind, placebo-controlled study to

address the latter point. Subjects

received a 3-ml stellate ganglion

injection of either lidocaine 2% or

saline before general anaesthesia

and surgery. The authors report a

statistically significant and clinically

relevant reduction in tramadol con-

sumption, administered via patient-

controlled analgesia, over the first

24 h postoperatively.

There are two conventional

ways of assessing the benefit of an

analgesic intervention: measuring

pain scores and/or recording anal-

gesic usage (preferably with a

patient-controlled analgesia system

rather than administered if and

when requested). Whilst pain scores

are commonly used as a research

tool, a statistically significant differ-

ence in pain scores may translate

poorly to an actual clinical benefit

for the patient. Furthermore, pain

scores are also hampered by intra-

and inter-individual variation in

scoring, making a change in median

pain scores across a group difficult

to interpret. In contrast, use of

analgesics can be used as a surro-

gate marker for pain, if one

assumes that the patient is ‘titrating’

the analgesic dose to provide an

acceptable level of analgesia. Whilst

this is not a direct evaluation of

subjective pain, it reflects the

patient experience, as the reduced

use of analgesic medication can be

thought to represent a reduction in

the pain experienced. In addition, it

addresses an important non-specific

aspect of managing pain, also inher-

ent in the concept of multi-modal

analgesia: that of a reduction in

analgesic doses in order to reduce

side-effects. The aim of the optimal

analgesic package is to get the best

analgesia for the least ‘cost’, if we

consider cost to include not just the

financial tariff but also complexity

and time, side-effects and risks.

Therefore Kumar et al.’s study aims

to address two questions. The first

is the usefulness of stellate ganglion

block before upper limb surgery in

reducing postoperative pain as

reflected by a reduction in self-

administered analgesic require-

ments. The second, and possibly

more important question, is its

exploration of the relationship

between the autonomic nervous sys-

tem, nociception and acute pain.

Acute pain and theautonomic nervoussystemIf asked, most clinicians would sup-

port the statement that a link exists

between the autonomic nervous sys-

tem and pain. Anaesthetic textbooks

and review articles alike repeatedly

reinforce this view by asserting that

pain stimulates a sympathetic stress

response. However, there is a lack

of clinical evidence to substantiate

this widely held belief [5]. More

importantly, there is even less evi-

dence to support the concept that

this interaction between nociceptive

transmission and the autonomic

nervous system works in a bidirec-

tional fashion; that is, nociception

stimulates the autonomic nervous

system and also conversely the

autonomic nervous system modu-

lates nociceptive processing. In this

regard, Kumar et al.’s work [1] is

essential in exploring an area of

pain and mechanistic nociceptive

© 2014 The Association of Anaesthetists of Great Britain and Ireland 945

Editorial Anaesthesia 2014, 69, 941–953

theory that is complex, incompletely

defined and inadequately explored.

Invasive placeboInterestingly, this paper has re-

ignited the emotive issue of the

appropriateness of including an

invasive placebo as part of a

research study assessing a therapeu-

tic intervention. The main argu-

ments against the use of invasive

placebos in clinical trials have been

outlined in 2011 in this journal [6,

7] and are revisited by Cyna & Tan

in their accompanying editorial

published in this issue of Anaesthe-

sia [8]. These articles focus on the

scientific and ethical implications of

performing a placebo nerve block

that is likely to yield no benefit to

the patient, yet is accompanied by

all the potential risks and complica-

tions. Although Cyna & Tan make

a strong argument against the inva-

sive placebo block, perhaps the

issue is not quite as clear-cut as one

might think at first. The potential

reasons for performing a placebo

block may be addressed by consid-

ering two questions: firstly, what is

the purpose of the invasive placebo

in this research context? And sec-

ondly, the more general question:

are invasive placebo interventions

ever appropriate in medical

research?

The purpose of theinvasive placeboAlthough this argument could be

accused of focussing on semantics,

it is important to appreciate the

true definition of a placebo in order

to evaluate the appropriateness of

the invasive placebo intervention.

Sites & Neal, in their editorial, use

the definition of a placebo from the

Merriam Webster online dictionary:

“an inert or harmless substance or

procedure” [7]. Ignoring the poten-

tial for complications of the nerve

block to cause harm, how does the

inertness of a substance square with

the well-known ‘placebo effect’? In

reality, the ability for a placebo to

be inert only needs to refer to the

context of the particular effect

expected. Therefore, taking a more

comprehensive definition from the

field of psychology (the discipline

integral in exploring and formulat-

ing our understanding of the

placebo effect), a placebo is “a sub-

stance or procedure that has no

inherent power to produce an effect

that is sought or expected” [9], and

the placebo effect is “a genuine psy-

chological or physiological effect

attributable to a substance or under-

going a procedure, but not due to

the inherent powers of that sub-

stance or procedure”. Taking these

two broader statements into

account allows us to appreciate that

an invasive procedure with a non-

active component can meet the cri-

terion of being a placebo.

The placebo effect is recognised

as being inconsistent and not asso-

ciated with a singular outcome.

Various mechanisms make up this

psychobiological phenomenon, and

the different potential effects are

dependent upon the disease context,

the system and the therapeutic

intervention being studied [10]. For

the purposes of the study by Kumar

et al. [1], the effect being evaluated

is that of placebo analgesia, the

administration of a placebo that

leads to pain relief and/or reduced

analgesic use. Much of the research

exploring the placebo effect has

been conducted in the field of pain

and analgesia. It is thought that the

phenomenon of placebo analgesia is

comprised of psychological mecha-

nisms including expectation, condi-

tioning and social learning, along

with neurobiological mechanisms

involving specific neurotransmitters

such as endogenous opioids and

dopamine, specific brain and spinal

cord regions, and finally the molec-

ular substrate effects of the placebo

analgesic itself [11].

As we have mentioned, Kumar

et al. aimed not only to explore the

analgesic effects of the stellate gan-

glion block but also the interaction

between the autonomic nervous sys-

tem and the nociceptive system.

The rationale behind this study

came from the original case series

by McDonnell et al. who specifically

targeted the stellate ganglion as a

means of isolating the contribution

of the sympathetic system to acute

nociceptive pain [2].

When designing clinical trials

to evaluate analgesic medications

or procedures, investigators need to

account for the uncertainty princi-

ple. This refers to the possibility

that the drug or intervention is not

directly modulating the pain path-

way, but instead influencing an

aspect of placebo analgesia, for

example the expectation pathways

[12]. This may not be important in

studies purely evaluating clinical

outcomes such as self-reported pain

intensity scores or analgesic doses,

but is an important confounding

factor if investigating the potential

underlying mechanisms of auto-

nomic modulation of nociception.

In this regard, Kumar et al. were

946 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2014, 69, 941–953 Editorial

required to include some methodo-

logical safeguard to account for this

confounder. Therefore, whilst Cyna

& Tan have criticised this study

design for including an invasive

procedure “to promote the non-

specific, non-biological (placebo)

treatment effect” [8], there is sound

scientific justification for its inclu-

sion. Their suggestion that the

study should also have included a

non-treatment control group is,

however, well founded; this would

have allowed the evaluation of

the effect of the needle insertion

per se.

Was the invasive placebojustified?The broader philosophical question

as to whether invasive placebo

interventions are ever justified in

medical research requires more

space than is available in this edito-

rial. However, one should also

remember the considerably greater

intervention of sham surgery, which

has a well-established place in sur-

gical research. A well known exam-

ple is a randomised study of

internal mammary artery ligation

for relief of angina pectoris. Some

patients received the surgical inci-

sion but without the arterial liga-

tion; they showed improvement in

exercise tolerance and symptoms,

and some also demonstrated

improvement in ECG patterns [13].

Sham surgery continues to be seen

as necessary for the evaluation of

benefit from surgical interventions;

last year the New England Journal

of Medicine published a multicentre,

randomised, double-blind, sham-

controlled trial in 146 patients [14].

The authors argued that this experi-

mental design increased the rigour

of their trial, which questioned the

usefulness of arthroscopic partial

meniscectomy.

What alternatives didKumar et al. have?If it is considered that Kumar et al.

should not have used an invasive

placebo, then alternative experimen-

tal pathways should be suggested.

Cyna & Tan propose that the inves-

tigators could have blinded the

patient, anaesthetist and assessor by

performing a stellate ganglion block

in the intervention group after

induction of general anaesthesia,

and subsequently placing identical

dressings on all participants. This

would address in part the ‘open-

hidden’ paradigm often imple-

mented whilst exploring the placebo

effect. In this circumstance, the

patient is unaware whether the

treatment has occurred or not by

its being administered in a ‘hidden’

manner; however, for true imple-

mentation of this rationale, a com-

parison would need to be made

against an ‘open’ group who knew

that they were receiving the stellate

ganglion block. In addition, it could

be argued that the active group

would be exposed to greater risk by

having the nerve block performed

under general anaesthesia rather

than while awake [15]. Is this ethi-

cally preferable to the invasive

placebo?

Unexplained issuesThe paper by Kumar et al. has

some limitations. One could argue

that their invasive placebo is not a

placebo in the truest sense. They

have used saline, a solution that

is – as far as we know – as ‘inert’

as possible when injected into

tissues. However, they could have

injected this into an area near but

not within the stellate ganglion,

avoiding some of the criticisms out-

lined by Cyna & Tan [8]. Further-

more, the authors draw broad

conclusions from somewhat limited

data. By confusing the term neuro-

inflammation (a process that is an

integral part of inflammatory pain)

with neuropathic pain (pain caused

by a lesion or disease of the

somatosensory nervous system) [16]

and using them interchangeably,

their explanation of how the auto-

nomic sympathetic nervous system

modulates neuropathic pain may be

flawed; the assumption that rest

pain reflects only neuropathic pain

is also without foundation.

Notwithstanding these prob-

lems, Kumar et al. have conducted

a well-designed study to answer a

very specific and scientifically

important question. Cyna & Tan

present their opinion on invasive

placebos, which lies at one end of a

spectrum [8], argued against by

other authors whom they quote.

Individual clinicians or research

ethics committees might take up

differing and even contradictory

positions on these matters, reflect-

ing in part the balance between

respecting study participants’ auton-

omy (the right to decide for them-

selves if properly informed) on the

one hand, and the desire to protect

them from risk (albeit paternalisti-

cally) on the other [17]. We are

now left with Kumar et al’s results

to fit into our understanding of

how the autonomic nervous system

may influence acute nociceptive

© 2014 The Association of Anaesthetists of Great Britain and Ireland 947

Editorial Anaesthesia 2014, 69, 941–953

pain and how this could aid in

optimising pain treatment.

Competing interestsNo external funding and no com-

peting interests declared.

H. LaycockWellcome Trust Clinical Fellow /ST6 AnaestheticsSection of Anaesthetics, PainMedicine and Intensive Care,Department of Surgery and Cancer,Imperial College London, Chelseaand Westminster HospitalLondon, UKS. M. KinsellaConsultant AnaesthetistDepartment of Anaesthesia,St Michael’s HospitalBristol, UKEmail:stephen.kinsella@uhbristol.nhs.uk

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doi:10.1111/anae.12803

Editorial

How important is peri-operative hypertension?

Pre-operative hypertension (Table 1)

[1] is associated with an increased

risk of peri-operative cardiac events

and/or mortality (for example [2–5]);

however, its omission from various

risk stratification algorithms, such as

the Revised Cardiac Risk Index [6]

amongst others, has precipitated a fall

in profile of this condition. This fall

in profile is at odds with its fre-

quency. In our recent work using

Hospitals Episode Statistics data from

England and Wales, 64%, 55% and

40% of patients undergoing cardiac

surgery [7], abdominal aortic aneu-

rysm repair [2] and major joint

arthroplasty [2], respectively, had a

diagnosis of hypertension.

In several studies, pre-operative

hypertension predicts mortality, or

mortality and major morbidity, in a

wide spectrum of surgery, from car-

diac [3, 8], to orthopaedic [2], to

day-case surgery [4]. This should be

unsurprising to anaesthetists for

Table 1 Classification of hyperten-sion [1].

Hypertensionstage

Clinic bloodpressure

1 > 140/90 mmHg2 > 160/100 mmHgSevere > 180/110 mmHg

948 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2014, 69, 941–953 Editorial