The AAPS Journal, Vol. 14, No.

3, September 2012 ( # 2012)

DOI: 10.1208/s12248-012-9346-5

Review Article
Theme: Human and Veterinary Therapeutics: Interspecies Extrapolations and Shared Challenges
Guest Editor: Marilyn Martinez

What about Pain in Disorders of Consciousness?

C. Schnakers,1,2,3,4,5 C. Chatelle,1,3 A. Demertzi,1,3 S. Majerus,2,4 and S. Laureys1,3,4

Received 30 November 2011; accepted 12 March 2012; published online 18 April 2012
Abstract. The management and treatment of acute pain is very difficult in non-communicative patients
with disorders of consciousness (i.e., vegetative state/unresponsive wakefulness syndrome (VS/UWS) and
minimally conscious state), creating an ethical dilemma for caregivers and an emotional burden among both
relatives and caregivers. In this review, we summarize recent findings about the neural substrates of
nociception and pain in VS/UWS patients as well as recent behavioral assessment methods of nociception
specifically designed for patients in altered states of consciousness. We will finally discuss implications for pain
treatment in these patients.
KEY WORDS: consciousness; minimally conscious state; nociception; pain; vegetative state.

INTRODUCTION associated with nociception and pain and the degree to which
it is preserved in vegetative and minimally conscious patients.
The management and treatment of acute pain is largely We also describe what are the behavioral signs of pain and
unsatisfying in severely brain-injured patients with disorders how these can be assessed using the Nociception Coma Scale.
of consciousness (DOC), creating an enormous ethical Finally, we discuss modalities of pain treatment in DOC
dilemma and emotional burden among caregivers and patients.
relatives. Even though recent neuroimaging findings have
shown functional communication in a small group of patients
NOCICEPTION AND PAIN
(2%) using mental imagery task (e.g., “imagine playing
tennis” to respond “yes”), typical bedside self-assessments
Nociception is “an actually or potentially tissue damag-
are impossible to obtain in these patients (1). Improving our
ing event transduced and encoded by nociceptors,” whereas
ability to assess and detect pain is hence crucial. Based on
pain is defined as “an unpleasant sensory and emotional
previous neuroimaging findings, we know that pain process-
experience associated with actual or potential tissue damage,
ing differs between the vegetative state (characterized by a
or described in terms of such damage” and hence constitutes
non-conscious reflexive behavioral pattern) and the minimal-
a first-person experience (2). The stimulation of nociceptors
ly conscious state (characterized by a fluctuant but reproduc-
leads to the transmission of the information via the spinotha-
ible conscious behavioral pattern). Such findings may have
lamic tract to the thalamus and afterwards to the cortex.
implications for treatments. On the other hand, behavioral
More exactly, the midbrain (i.e., periaqueductal matter) and
assessment methods may be used to detect pain behaviors, to
the thalamus (which participates in the increase of arousal
signal the need for intervention, and to evaluate treatment
following a nociceptive stimulus) are thought to be involved
effectiveness as numerous pain scales have been developed
in the modulation of reflex responses to nociceptive stimuli.
for non-communicative patients such as demented elderly,
Nociception hence refers to the perception—conscious or not
newborns/preverbal children, or sedated/intubated patients.
—of a nociceptive stimulus (2,3). In contrast, pain processing
In this context, the Nociception Coma Scale has been recently
involves more extensive cortical activation incorporating
validated to assess and detect behavioral signs of pain in
sensory discriminative (or lateral) systems as well as motiva-
DOC patients. In this review, we summarize brain functioning
tional-affective and cognitive-evaluative (or medial) systems.
1
The primary and secondary somatosensory cortices partici-
Coma Science Group, Cyclotron Research Centre, University of pate in the sensory–discriminative aspects of pain processing,
Liège, Sart Tilman, B30, 4000 Liège, Belgium.
2 whereas the cingulate, insula, and prefrontal cortices are
Department of Psychology, Cognition & Behavior, University of
considered to be involved in the cognitive and affective
Liège, Liège, Belgium.
3
Department of Neurology, University Hospital of Sart Tilman, aspects of pain processing (3–5). Beyond perception, a well-
Liège, Belgium. characterized anatomical network, “the descending pain
4
Fund for Scientific Research—FNRS, Brussels, Belgium. modulatory system,” enables the regulation (facilitation or
5
To whom correspondence should be addressed. (e-mail: inhibition) of nociceptive processing. The cingulo-frontal
c.schnakers@ulg.ac.be) cortex may exert top-down influences on the periaqueductal

437 1550-7416/12/0300-0437/0 # 2012 American Association of Pharmaceutical Scientists

438 Schnakers et al.

matter and posterior thalamus to gate pain modulation (6–8). central processing of pain using electrical stimulation.
Previous studies have also shown the role of the prefrontal Activation was found not only in the primary somatosensory
cortex in mediating or controlling interactions in brain areas cortex but also in the secondary somatosensory cortex, in the
related to pain which lead to perceptual changes in response cingulate cortex contralateral to the stimulus, and in the
to identical nociceptive inputs (5). posterior insula ipsilateral to the stimulus, suggesting that
The involvement of all these areas is related to what is residual perception could be present for at least some of these
called the “pain matrix.” Not only the activation but also the patients. The activated pain network, however, was very
connections within this network seem to be involved in incomplete relative to typical activation patterns, and hence
conscious pain perception. Indeed, the vast majority of conscious pain perception in these patients is less likely. Boly
neuroscientific evidence points to the critical role of thala- et al. (24) found that even though many regions of the pain
mocortical and cortico-cortical (i.e., frontoparietal areas) network are activated, they are disconnected from each other.
interactions in conscious perception (9–11). The activated primary somatosensory cortex was functionally
disconnected from the secondary somatosensory, bilateral
PAIN IN NON-CONSCIOUS VERSUS CONSCIOUS posterior parietal, premotor, polysensory superior temporal,
PATIENTS and prefrontal cortices. These results were also obtained
using auditory stimulation (activation solely in the primary
auditory cortex disconnected from high-order associative cortices)
Vegetative State (25,26) or proprioceptive stimulation (hypermetabolism in
the brainstem isolated from the precuneal cortices) (27).
The term “vegetative state” (VS) was defined to describe More exactly, recent findings suggest that VS/UWS patients
“an organic body capable of growth and development but present a severe impairment of backward connectivity in
devoid of sensation and thought” (12). This state implies the high-order associative cortices (i.e., from frontal to
preservation of autonomic functions (e.g., cardiovascular temporal areas) which may be crucial for integrative brain
regulation, thermoregulation) in the absence of conscious- processing leading to consciousness (28). In the VS/UWS
ness. Regarding the negative associations intrinsic to the term state, primary cortical activation hence appears to be
“vegetative state,” it has been recently proposed to rather use isolated from higher-order associative cortical activity,
the term “unresponsive wakefulness syndrome” (UWS) (13). suggesting partial non-integrated and, hence, most likely
Behaviorally, patients in VS/UWS open their eyes spontane- non-conscious pain processing (see Fig. 1).
ously or in response to stimulation, but they only show reflex
behaviors, unrelated to the environment (14). When there is
no recovery 3 months after a non-traumatic injury (i.e.,
anoxia) or 1 year after a traumatic injury, the state is
considered permanent, and only then can the ethical and
legal issues around withdrawal of treatment be discussed
(15,16).
In VS/UWS patients, metabolic dysfunctions were
reported in areas such as the lateral and medial frontal
regions bilaterally, parietotemporal and posterior parietal
areas bilaterally, and the posterior cingulate and precuneal
cortices (17,18) which are mostly involved in the default
network. This network is the most active at rest and seems
implicated in self-related thoughts and, hence, in self-
awareness (19). According to previous studies, the connec-
tivity in the default network seems negatively correlated
with the degree of clinical consciousness impairment and
hence less important in VS/UWS as compared to conscious
patients (20,21). More particularly, the connectivity in the
precuneus/anterior cingulate cortex (20,21) and in the
dorsolateral prefrontal cortex (21) was found to be
significantly weaker in VS/UWS patients as compared with
minimally conscious patients.
Laureys et al. (22) directly investigated the central
processing of nociceptive stimuli by using positron emission
tomography (PET). Electrical stimulations of the median
nerve were administered to 15 VS/UWS patients and
compared with 15 healthy controls. Nociceptive stimuli
activated the midbrain, contralateral thalamus, and primary
Fig. 1. As compared to healthy volunteers, patients in a vegetative
somatosensory cortex in each and every VS/UWS patient, state/unresponsive wakefulness syndrome only show partial activa-
suggesting relatively preserved nociception and at least tion encompassing the primary somatosensory cortex in response to
partial sensory-discriminative pain processing. In a study of nociceptive stimuli. In minimally conscious patients, those stimuli
Kassubek et al. (23), seven post-anoxic permanent VS/UWS activate a widespread network similar to healthy volunteers [adapted
patients were investigated using 15O-H2O PET to analyze the from (22) and (34)]
What about Pain in Disorders of Consciousness? 439

Table I. Behavioral Responses (i.e., Facial Expression, Vocalization/Verbalization, Body Movements, Consolability, Arousal, Physiological Parameters, and Activity Pattern) Assessed by Pain

Activity
pattern
Minimally Conscious State

√
√

√
√

√
Patients in a minimally conscious state (MCS) show
fluctuating but reproducible signs of awareness. These patients

Physiological
parameters
can manifest emotional and oriented behavioral responses such
as response to verbal order, object manipulation, visual pursuit,

Scales Which Were Developed for Non-communicative Patients Such as Demented Elderly, Newborns/Preverbal Children, or Sedated/Intubated Patients (38–40)
or non-functional communication (29). Recently, this clinical

√
√

√
√

√
entity has been subcategorized in MCS+ and MCS− based on
the difference of functional neuroanatomy in the presence/

Arousal
absence of response to verbal order (i.e., language network,
premotor, pre-supplementary motor, and sensorimotor cortices)

√
(30). Nevertheless, behavioral responses can fluctuate in time,

Consolability
which makes the detection of consciousness challenging. A
recent study has shown that about 40 % of severely brain-
injured patients are erroneously diagnosed as being non-
conscious or VS/UWS, underlining the importance of assessing

√
√
carefully these patients before making a diagnosis (31).

movements
In patients having recovered from the VS/UWS state, there
is not only a return to normal metabolism in associative areas

Body
(particularly, precuneus/posterior cingulate cortex) (32) but

√
√

√
√
√
√
√
√
√
√

√
√
√
also, and importantly, a reestablishment of the correlation
between these areas and the thalamus (33). As compared with

Verbalization
Vocalization/
VS/UWS patients, the connectivity in the default network of
MCS patients is also more important even if inferior to what is
observed in healthy volunteers (20). The functional connectivity

√
√
√
√
√

√
√
√
√
between thalamocortical areas and cortico-cortical areas is
therefore crucial to consciousness recovery.
expression
Using nociceptive stimuli, Boly et al. (34) showed brain
Facial

activation similar to controls in five MCS patients with

involvement of the thalamus, the primary somatosensory cortex,

√
√
√
√
√
√

√
√
√
√

√
√
√
the secondary somatosensory cortex or insula, the posterior

NOPPAIN The Non-Communicative Patient’s Pain Assessment Instrument) (81)

cingulate cortex/precuneus, and the anterior cingulate area; the
PACSLAC (Pain Assessment Checklist for Seniors with Limited Ability

latter area is known to be linked to pain unpleasantness

CHEOPS (Children’s Hospital of Eastern Ontario Pain Scale) (86)

perception and provides this evidence for the presence of
ECPA (L’Echelle Comportementale pour Personne Agées) (79)

cognitive and affective processing. Larger cortical activation in

MCS versus VS/UWS has also been observed using auditory
PAINAD (Pain Assessment in Advanced Dementia) (80)

stimulation (25,26,35,36). In addition to this increased brain

activation, a better connectivity between the primary cortex and
CNPI (Checklist of Nonverbal Pain Indicators) (82)

associative cortices was noticed in MCS as compared with VS/ FLACC(Face, Legs, Arms, Cry, Consolability) (87)
UWS (24,34). These data suggest that MCS patients may have PPPM (Parents’ Postoperative Pain Measure) (88)
sufficient cortical integration and access to afferent information
PIPP (Premature Infant Pain Profile) (84)

to allow awareness of nociceptive stimuli (see Fig. 1).

NIPS (Neonatal Infant Pain Scale) (85)

BEHAVIORAL SIGNS OF PAIN

BPS (Behavioral Pain Scale) (89)

Pain is a subjective experience. Severely brain-injured

patients are nevertheless unable to communicate their feelings
to Communicate) (78)

and possible pain experiences. According to the International

COMFORT Scale (90)
Abbey Pain Scale (83)

Association for the Study of Pain, the inability to communicate

DOLOPLUS2 (77)

verbally does not exclude the possibility that an individual is

experiencing pain and needs appropriate pain-relieving treatment
Pain scales

(3). The main way to detect conscious perception in DOC

patients is based on serial bedside behavioral assessment.
Standardized behavioral scales usually include various languages,
auditory, visual, and somatosensory stimuli in order to test the
reaction of the patient to these stimuli and to detect signs of
Newborns/preverbal
Demented elderly

Sedated/intubated

consciousness. However, few instruments have been developed

and validated to assess pain in VS/UWS or MCS patients (37).
At the same time, numerous pain scales have been
Population

children

patients

developed for non-communicative patients such as demented

elderly, newborns/preverbal children, or sedated/intubated
patients. Table I presents a list of behavioral scales existing for
440
assessing these patients (n=14) and mentions, for each of these
scales, which behaviors are assessed among the following ones:
(a) facial expression (e.g., grimaces or any distorted facial
expression); (b) vocalizations/verbalizations (e.g., groaning, cries,
calling out, or inappropriate words/insults); (c) body movements
(e.g., rigid, antalgic body posture, bracing, rubbing, localization of
painful area, agitation or restlessness); (d) consolability (i.e.,
number of tactile or auditory stimulations needed to reassure the
patient); (e) arousal; (f) physiological parameters (e.g., breathing,
cardiac frequency or arterial pressure); and (g) changes in activity
pattern (e.g., appetite and sleep changes or changes in social
interaction) (38–40). In accordance with Table I, the most
frequent behaviors assessed by those scales are facial expression
and body movements (in 13 out of 14 scales) as well as
vocalizations/verbalizations (in 10 out 14 scales). Keefe et al.
previously mentioned that a person who experiences pain may
vocalize and exhibit pain-related body postures or facial expres-
sions. These verbal and nonverbal behaviors have been called
“pain behaviors” (41,42). Individuals have several ways to deal
with injury, many of which rely on motor responses. Withdrawal
reflexes, for example, exist from the earliest moments and allow
us to move away from sources of pain. Considering nociceptive
stimuli, three types of motor responses are usually considered
when assessing severely brain-injured patients: stereotypical
responses (i.e., slow generalized flexion or extension of the upper
and lower extremities), flexion withdrawal (i.e., the limb moves
away from the point of stimulation), and localization responses
(i.e., the non-stimulated limb must cross the body’s midline or
locate and make contact with the stimulated body part at the
point of stimulation) (37,40). These responses are respectively
linked to brainstem and subcortical or cortical activity, respec-
tively. Localization response to pain is the only motor response
considered indicative of conscious perception by international
guidelines (14). In addition to motor responses, individuals may
use language to express the presence, the intensity, and the
characteristics of the perceived pain. Severely brain-injured
patients are nevertheless not able to verbally report pain. Non-
communicative patients can nevertheless produce vocalizations in
response to a nociceptive stimulus, indicating potential pain
experiences.
Finally, in response to pain, individuals will manifest
involuntary facial expressions of pain such as grimaces. This
behavior has been recognized as providing the most specific
and sensitive nonverbal cues for pain and is the most common
component assessed by behavioral pain assessment tools for
non-communicative patients (43–45). Previous scientific
investigations have shown that the experience of pain is often
represented by changes in facial expression and is a consistent
marker of pain across the life span, cultures, and species
(42,46). Nonverbal expressive behavior may hence provide
important information about pain not available through
verbal report. Yet, little is known about its neurobiological
basis. Previous studies have shown that, when observing
others’ facial expression of pain, healthy volunteers activated
areas which are involved in the pain matrix and are linked to
self-assessment of pain such as the anterior cingulate cortex
and the insula (47–50). The brain network involved in this
behavior has therefore mainly been studied not directly but
through mirroring mechanisms such as the motor mirror-
neuron system, which is assumed to be related to other
people’s actions, percepts, and feelings (51). According to our
Schnakers et al.
knowledge, only one study investigated brain mechanisms
underlying the regulation of facial expressiveness to acute
pain. Kunz et al. (52) considered facial responses, pain ratings,
and brain activity (BOLD-fMRI) evoked by nociceptive heat
in 34 human volunteers. Facial expressiveness was positively
correlated with pain-related areas such as the bilateral
primary somatosensory cortex and bilateral posterior insula,
indicating that spontaneous pain expression reflects activity
within nociceptive pathways. Even if grimacing is considered
as an indicator of pain, the Multi-Society Task Force on PVS
did not consider it as a necessary sign of conscious perception
as they can occur reflexively through subcortical pathways in the
thalamus and limbic system (14). Patients showing no sign of
consciousness except grimaces to nociceptive stimuli can
therefore be diagnosed as being in VS/UWS. Nevertheless, until
now, no study has investigated the frequency of such behavior in
conscious (MCS) versus non-conscious (VS/UWS) patients.
We will also mention that several pain scales for non-
communicative patients include the assessment of physiolog-
ical parameters such as the respiratory and cardiac frequency
rate or arterial blood pressure as these may constitute more
objective indicators of pain (53). However, these parameters
seem insufficiently sensitive for pain assessment. Indeed,
stress, medication, and medical complication, but also brain
lesions affecting autonomic functions, may influence these
parameters and bias the assessment (54). Additionally, these
responses may be discarded due to the difficulty of reliably
assessing breathing and cardiac patterns in patients not
benefiting from monitoring devices (40).
Detection of Pain Behaviors in VS/UWS and MCS Patients:
The Nociception Coma Scale
As already noted, DOC patients are unable to commu-
nicate their feelings and their perception of pain. It is hence
important to develop sensitive instruments to detect pain
behaviors in these patients. In this context, the Nociception
Coma Scale (NCS) was recently validated (55). This scale
includes the observation of motor, verbal, and visual
responses as well as facial expression. The total score varies
from 0 to 12. A validation study of the NCS was performed by
observing the responses of 48 VS/UWS and MCS patients to
a nociceptive stimulus (i.e., pressure applied to the bed of the
fingernail). The results showed a good inter-rater agreement
and concurrent validity between NCS and other pain scales
validated for demented elderly patients and newborns/
preverbal children, suggesting good psychometric qualities
of the NCS. Moreover, the NCS total scores, but not those of
the other pain scales, were significantly higher in MCS versus
VS/UWS patients. According to our results, the NCS hence
represents a sensitive tool adapted for detecting pain behaviors
in severely brain-injured patients. For research purposes, the
NCS may also represent an interesting tool for better charac-
terizing behavioral patterns presented by VS/UWS and MCS
patients in response to nociceptive stimuli. As said above, a
clinical sign such as grimacing is often considered as a behavioral
sign of pain when assessing non-communicative patients (42–
46). This behavior is not considered as a sign of consciousness by
the Multi-Society Task Force (14). However, clinical data
considering the proportion of VS/UWS and MCS patients
demonstrating this behavior do not exist.
What about Pain in Disorders of Consciousness?
In this context, we have retrospectively compared the
frequency of grimaces observed with the NCS in response
to nociceptive versus non-nociceptive stimuli. The non-
nociceptive stimuli consisted in applying taps on the
patient’s shoulder, whereas the nociceptive stimuli consisted in
applying a pressure on the patient’s fingernail (in the absence of
upper limb contusions, fractures, or flaccid paralysis) (40).
Behavioral responses were observed for 10 s post-stimulus in
both conditions. In order to ensure a sufficient level of arousal,
each condition was administered while patients showed
spontaneous eye opening. We collected the responses of 64
severely brain-injured patients (age range, 20–82 years; 24
women, 22 with a traumatic etiology; time since onset,
3 days to 9 years) of whom 27 were VS/UWS and 37 were
MCS (based on behavioral assessment performed using the
Coma Recovery Scale-Revised) (55,56) (XXth World Congress
of Neurology, 2011). Grimaces were presented more frequent-
ly in response to nociceptive stimuli than in response to
non-nociceptive stimuli in both groups (i.e., 48 % versus
4 % for VS/UWS and 65 % versus 3 % for MCS,
respectively; see Fig. 2). We have performed chi-square
tests to verify whether the proportion of grimaces was
different according to the patient’s consciousness level (i.e.,
VS/UWS versus MCS) and the etiology (i.e., traumatic versus
non-traumatic). We also performed a one-way ANOVA for
testing whether the time since onset (in days) differs according
to the presence or absence of grimaces. As regards the
consciousness level, facial expressions of pain were not
observed more frequently in MCS than VS/UWS patients
(χ2 = 2.44, p = 0.12). Out of 27 VS/UWS patients, nine
patients were considered in a permanent VS/UWS state
(PVS). Among these, 33 % (n=3, all with anoxic injury; time
since onset, 13, 21, and 41 months, respectively) presented
grimaces solely in response to nociceptive stimuli. Finally, we
observed no significant difference according to the etiology
(traumatic versus non-traumatic; χ2 =.25, p=0.61) or according
to the time since onset (F=2.69, p=0.11).
According to our results, facial expressions such as
grimaces are observed more frequently in response to
Fig. 2. Proportion of non-conscious (VS/UWS) and conscious (MCS)
patients showing grimaces in response to both tactile (i.e., non-
nociceptive) and nociceptive stimuli
441
nociceptive stimuli than in response to non-nociceptive ones.
However, this behavior is not observed more frequently in
patients diagnosed as being conscious (i.e., MCS) than in
patients diagnosed as being non-conscious (i.e., VS/UWS).
This behavior is also not more frequently observed in patients
who have a better chance of recovery, such as patients with a
traumatic etiology and who are in the acute stage (12). On the
contrary, in our sample, grimaces are observed in 33 % of the
PVS patients, suggesting it is linked to non-conscious brain
processing. According to Kunz et al. (52), the primary
somatosensory cortex and the posterior insula seem related
to facial expressiveness. Whereas the primary somatosensory
cortex involves basic sensory-discriminative pain processing,
the insula involves high-order cognitive and affective pain
processing. As regards to previous studies, it seems that only
the primary somatosensory cortex is activated in response to
nociceptive stimuli in non-conscious VS/UWS patients. The
study of Kassubek et al. (23) also showed activation in the
posterior insula ipsilateral to the stimulus (i.e., electrical
stimulation applied to the median nerve area at the left volar
distal forearm), but this result was not found in the other
studies. Moreover, as Boly et al. (24,26) pointed out, not only
the activation of brain areas but also their functional
connectivity are crucial for conscious perception. Future
investigations will hence have to determine whether grimaces
observed in VS/UWS and MCS patients are supported by the
same neural networks or not and whether the behavioral
characteristics of grimaces differ according to the patient’s
consciousness level using, for instance, an automated facial
coding system (e.g., Facial Action Coding System) (57).
PAIN TREATMENT
In the acute stage, pain may be caused by fractures,
intra-abdominal injuries, soft tissue injuries, and pain
associated with invasive procedures. In the chronic stage,
pain may be due to spasticity, contractures, pressure sores,
soft tissue ischemia, peripheral nerve injuries, and postsur-
gical incisional pain, among numerous possibilities (37).
Besides, well-documented pain history (e.g., osteoarthritis,
rheumatoid arthritis, or gout) is critical in order to detect
the presence of additional preexisting pain generators and,
in DOC patients, will likely be obtained from the family or
the legal surrogate.
Pain management has to be provided in the presence of
one of these potentials generators of pain, particularly when
behavioral signs of pain are observed during the nursing care
or during the mobilization/palpation of potential painful
areas. Spontaneous behavioral signs of pain can be taken
into considerations. However, the presence of such signs
could be unrelated to pain (e.g., pathological activation of
subcortical areas leading to constant but not appropriate
cries) and has therefore to be replicated in a pain-related
condition (i.e., mobilization/palpation). In this context, the
NCS may constitute a helpful instrument, for monitoring pain
behavior on a daily basis, at rest and during the nursing care.
A sudden increase of the NCS total score will alert the
clinician of a potential presence of pain. Additional inves-
tigations may then be performed to identify its origin/
localization (e.g., by using mobilization/palpation or CT/
MRI scans). The adapted treatment will subsequently be
442
administered. The balance between under-treatment and
over-treatment is nevertheless difficult to keep (40). In case
of under-treatment, the presence of pain could affect the
patient’s recovery, whereas an over-treatment could minimize
cognitive recovery and potentially affect brain plasticity.
Indeed, medications that potentially alter neurological assess-
ment should be used with caution in DOC patients. Consid-
eration should be given to medications with reversible effects
(e.g., opiate reversal with naltrexone) whenever there is
question of medication effects versus ongoing deterioration
of neurological status (37). The long-term effect of prolonged
antalgic treatment on brain plasticity and recovery after a
severe brain injury is also largely unknown. Studies in animals
suggest potential adverse long-term effects of morphine on
brain (54,58) and cognitive (59,60) functioning in the adult
rat. The opioid system also modulates neural proliferation
(61) inducing, for example, the apoptosis of human microglial
cells (62) or neuronal degeneration in rats (54,58). The type
of treatment and its duration has therefore to be cautiously
discussed with the medical team and the family before being
applied and has to be regularly reconsidered.
Unfortunately, no real consensus exists as regards pain
treatment in DOC patients (40). Considering previous findings,
a more preserved pain processing network seems to be observed
in MCS patients as compared with VS/UWS patients. One could
interpret these results as an argument for prioritizing pain
treatment in MCS patients. However, clinicians have to be
cautious as regards the diagnosis. Indeed, Schnakers et al. (31)
have recently shown a misdiagnosis rate of 41 % among DOC
patients: signs of consciousness being easily missed due to
vigilance fluctuations, motor deficits, or the absence of the use of
sensitive standardized coma scales, among other explanations.
Moreover, an increased number of recent studies have
shown voluntary brain activity in the absence of any
oriented motor/verbal responses in patients diagnosed as
being non-conscious (1,32,63–66). According to the largest
sample study (n=54), about 10 % (2 out of 23) of VS/
UWS patients are able to voluntarily perform a task
mentally (e.g., mental imagery) (1). These results open the
discussion about the presence of consciousness in some of
the patients showing no oriented/voluntary behaviors (67).
Additional investigations are warranted in order to better
characterize this new clinical entity, recently called the
“functional locked-in syndrome” (i.e., patients whose
consciousness is only detectable via paramedical testing) (68).
Without the use of technologies such as neuroimaging or
electrophysiology, it is currently difficult for clinicians to identify
this population. Therefore, considering the levels of clinical
uncertainty, pain treatment should be considered in all patients
diagnosed as being in a VS/UWS or MCS. Future discussion will
have to establish clearer guidelines in order to help clinicians not
only when managing pain in DOC patients but also when
managing end-of-life decisions in these patients. Indeed, clini-
cians want to be certain that an individual is not in pain or
suffering when making crucial clinical decisions such as end-of-
life decision (e.g., Terry Schiavo died from dehydration without
administration of opiates as she was diagnosed as VS/UWS by
the High Court’s experts) (69).
Given that we may underestimate the cognitive abilities
of DOC patients, additional studies have to be performed to
better define remnant cognition in these patients and its
Schnakers et al.
potential relation to suffering (40). Another challenge will be
the detection of chronic pain in DOC patients. Indeed,
chronic pain is a common and persistent problem (i.e.,
prevalence of 37.3–41.1 %) (70) and has to be considered in
patients suffering a brain injury (71). Headache after a
traumatic brain injury is frequent (i.e., prevalence of 50 %)
(72,73). Chronic pain may follow central nervous system
damages (thalamic pain due to a stroke or a traumatic brain
injury with diffuse axonal injury) (74) or peripheral damages,
leading to changes in central nervous system pain processing
(accompanied by central sensitization and hyperalgesia/allo-
dynia, e.g., complex regional pain syndrome) (75). The
existence of chronic pain in severely brain-injured patients
cannot be excluded, but is nearly impossible to detect in these
non-communicative patients. The sustained presence of pain
behaviors without stimulation or without documented/appar-
ent pain could reflect a potential presence of chronic pain.
However, it is difficult to know whether these observations
are truly related to pain or not. Future investigations will
have to characterize the “pain matrix” activation in patients
presenting such a profile. More globally, as very few studies
have been performed until now, further research is warranted
to better understand remnant pain processing in DOC
patients. Studying pain in such vulnerable population is
obviously ethically difficult. Nociceptive stimuli are requested
and are administered without the direct patients’ agreement,
but with the consent of the legal surrogate. A possible
alternative is the indirect study of the preservation of the
pain matrix by studying the brain metabolism at rest and
comparing the functioning of the pain-related brain network
in typical permanent VS/UWS patients, MCS patients, and
healthy volunteers. This will nevertheless not replace activa-
tion studies, and further discussions are needed in order to
provide guidelines to researchers and increase the amount of
studies performed on this topic (76).
CONCLUSION
Pain treatment in severely brain-injured patients has to
be guided by ethical principles of beneficence and non-
maleficence. Even if neuroimaging findings tend to show that
VS/UWS patients have incomplete pain perception, further
investigations are crucially needed. Misdiagnosis rates are
high, and recent studies have shown voluntary brain activity
in patients behaviorally diagnosed as being in a VS/UWS
state. Therefore, as regards the current uncertainty, we should
take the safer course by treating all DOC patients as if they
had the potential to perceive pain and suffer.
ACKNOWLEDGMENTS
This study was supported by the Belgian Federal Public
Health, the National Funds for Scientific Research (FNRS),
James S. McDonnell Foundation, Mind Science Foundation,
European Commission (Mindbridge, DISCOS, DECODER
& COST), Concerted Research Action (ARC 06/11-340),
Public Utility Foundation “Université Européenne du Tra-
vail,” “Fondazione Europea di Ricerca Biomedica,” and the
University of Liège. CS is a Postdoctoral Researcher, CC and
AD are research fellows, and SM and SL are senior research
associates at FNRS.
What about Pain in Disorders of Consciousness?
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