Journal of Psychosomatic Research 78 (2015) 228–236

Contents lists available at ScienceDirect

Journal of Psychosomatic Research

The common link between functional somatic syndromes may be

central sensitisation
Julius H. Bourke a,⁎, Richard M. Langford b, Peter D. White a
a
Centre for Psychiatry, Wolfson Institute for Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University London, UK
b
Pain and Anaesthesia Research Centre, St. Bartholomew's Hospital, London EC1A 7BE, UK

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Functional somatic syndromes are common and disabling conditions that all include chronic pain, and
Received 26 August 2014 which may be related to central nervous system sensitisation. Here, we address the concept of central sensitisa-
Received in revised form 23 December 2014 tion as a physiological basis for the functional somatic syndromes.
Accepted 4 January 2015 Methods: A narrative review of the current literature on central sensitisation and physiological studies in the
functional somatic syndromes.
Keywords:
Results: Central sensitisation may be a common neurophysiological process that is able to explain non-painful
Central sensitisation
Chronic pain
as well as painful symptoms in these disorders. Furthermore, central sensitisation may represent an
Functional somatic syndromes endophenotypic vulnerability to the development of these syndromes that potentially explains why they cluster
Neurophysiology together.
Pathophysiology Conclusions: Further research is needed to verify these findings, including prospective studies and the
standardisation of combined methods of investigation in the study of central sensitisation in functional somatic
syndromes. In turn, this may lead to new explanatory mechanisms and treatments being evaluated. Our conclu-
sions add to the debate over the nomenclature of these syndromes but importantly also provide an explanation
for our patients.
© 2015 Elsevier Inc. All rights reserved.

Introduction disorders, grouped together by common symptoms, but separated by

individual pathophysiologies [6]. These opposing arguments have led
Functional somatic syndromes (FSS) are conditions in which physi- to the coloquialised question as to whether we should ‘lump’ these
cal symptoms are not fully explained by an established, alternative disorders together, or ‘split’ them apart [6,7].
medical disorder (Table 1). FSS are common, disabling, and incur a Patients with one FSS are more likely to also suffer from another [8].
significant use of health care resources and are a source of financial For example 51% of patients with chronic fatigue syndrome (CFS) and
burden borne by patients, their families and society [1,2]. The conceptu- 49% of patient with fibromyalgia (FM) also have irritable bowel
alisation of these disorders as being ‘unexplained’ is not only a potential syndrome (IBS) [9]. This may be because these disorders seem to
barrier to improved care [3], but it is also challenged by our increasing share common predisposing risk factors (but not precipitants) [10,11].
understanding of them from a neurophysiological perspective. These cited studies examined patients with either IBS or CFS and report-
ed predisposing factors common to both conditions (other FSS and
Multiple and separate, or single and together? mood disorders), in addition to precipitating factors that differentiated
them (different infectious agents) [10,11].
The nosology of FSS is undetermined. This is in part due to uncertain-
ty regarding both pathophysiology and aetiology as reflected in the Chronic pain and the functional somatic syndromes
DSM V review of the classification of somatic syndromes [4] and the
borderland between mental and physical health that they inhabit [5]. Research into the pathophysiological mechanisms of FSS is made
FSS encompass a wide range of apparently distinct syndromes difficult by the nature of these disorders, which represent symptom
(Table 1). However, symptoms overlap between the disorders to such clusters across a wide array of different systems. One approach has
an extent that some have suggested that there is one generic FSS, rather been to look at the individual symptoms that predominate in a given
than many [6], whilst others have proposed that FSS are discrete FSS, e.g. fatigue in CFS or bowel symptoms in IBS. These symptoms
generally involve a combination of different physiological, cognitive
⁎ Corresponding author. Fax: +44 20 346 57082. and affective drivers, representing an interaction between the central
E-mail address: [email protected] (J.H. Bourke). nervous system (CNS) and the dominant system to which the defining

http://dx.doi.org/10.1016/j.jpsychores.2015.01.003
0022-3999/© 2015 Elsevier Inc. All rights reserved.
 J.H. Bourke et al. / Journal of Psychosomatic Research 78 (2015) 228–236 229

Table 1 The superficial dorsal horn is comprised of lamina I and II. Lamina I
Examples of functional somatic syndromes. plays a key role in the modulation of pain transmission with 85% of its
• Irritable bowel syndrome neurons being nociceptive with a high threshold for excitation, whilst
• Fibromyalgia only 15% have a wide dynamic range, responding to lower thresholds.
• Chronic fatigue syndrome In comparison, the majority of neurons in lamina V, located in the
• Temporomandibular joint disorder
neck of the dorsal horn, also have a wide dynamic range, and so are
• Idiopathic lower back pain
• Multiple chemical sensitivity predominantly non-nociceptive. Neurons from lamina II terminate
• Tension-type headaches locally within the dorsal horn, whilst those from lamina I have long
• Interstitial cystitis axons that travel in the parabrachial pathway [18]. This pathway
• Chronic pelvic pain
along with the spinothalamic tract, carries information to the
• Myofascial pain syndrome
parabrachial area in the midbrain from where it projects to higher
cortical centres, including the hypothalamus, the amygdala and parts
symptoms are attributed. Defining and then modelling diffuse of the thalamus [19]. These higher centres form part of a non-specific
symptoms such as fatigue is particularly difficult. Pain, on the other network of structures previously referred to as a ‘neuromatrix’ [20]
hand, represents an easier target. It is a diagnostic criterion of all FSS that is thought to be involved in, but not specific to the perception of
and the commonest symptom overall [12]. As such, it represents a pain [21]. The different structures within this network contribute to
unifying symptom, a better understanding of which may improve the evaluative, affective and sensory interpretation of the painful stim-
our understanding of FSS as a whole. To this end, some authors have uli. The parabrachial pathway also projects to other centres involved
considered these syndromes together as disorders that reflect a state in the descending control of pain, including the rostro-ventral medulla
of CNS mediated hypersensitivity to painful stimuli [13,14] — ‘central and the periaqueductal grey area [22]. These descending control mech-
sensitisation’ (CS). anisms are responsible for a reduction in the sensation of pain and the
inhibition of its spread upon the perception of pain (see Fig. 1a).
Chronic pain and central sensitisation Pain perception exhibits neuroplasticity, whereby repeated
nociception may result in either habituation (reduced response) or
Pain represents an experience that is influenced not only by sensa- sensitisation (increased response). As such, continued stimulation
tion, but also by context and prior experience. The experience of pain may result in increased neuronal responsivity or sensitisation [23],
is distinct from nociception [15]: nociception describes afferent neural depending on the intensity and temporal features of the stimulation.
activity transmitting sensory information about stimuli that have the CS refers to a ‘pain phenotype’ generated by processes that result in
potential to cause tissue damage [16], whereas pain is an emergent the amplification of the pain, which are thought to underlie many
phenomenon, a conscious experience that requires cortical activity [17], chronic pain states. This sensitised state involves both spinal mecha-
and which can occur in the absence of nociception. Acute pain originates nisms, at the level of the dorsal horn and below and supraspinal mech-
from nociceptors, activating two types of nerve fibre (low threshold fast anisms that involve the disproportionately augmented response of a
A delta fibres and high threshold slow unmyelinated C fibres). These network of higher brain centres [20], with the latter subsequently
fibres synapse onto both wide dynamic range (those that are responsive contributing to the descending control of afferent spinal neurotransmis-
to all sensory modalities and to a broad range stimulus intensity) and sion. CS therefore involves a dual process of spinal sensitisation and
high-threshold neurons in the dorsal horn of the spinal cord, depending augmentation of this neural network. It is important to note, however
on the nature of the painful stimulus encountered. that these processes occur in parallel rather than in series and that

Fig. 1. a&b: Spinal sensitisation: Ascending and descending mechanisms involved in pain control. a: A painful stimulus is able to activate peripheral nociceptors that in turn activate
nociceptive neurons in the superficial dorsal horn of the spinal cord. Lamina II neurons project in the spinoreticular and spinothalamic tracts to the brainstem and higher cortical centres.
At the level of the brainstem, descending inhibitory mechanisms are activated involving monoamine and opioid neurotransmitter systems (conditioned pain modulation) in tandem with
a reduction in descending facilitatory mechanisms. In turn these act to reduce pain and prevent its spread to neighbouring areas. With this system intact, upon repeat stimulation a
habituation response is facilitated, whereby the same stimulus intensity results in the same or less painful sensation. b: In a sensitised state, non-painful stimuli are able to activate
nociceptive specific dorsal horn cells. A clinical consequence of this is the experience of pain on non-painful stimulation — allodynia. This in turn results in greater activity in ascending
pathways to the brainstem. There is a reduced response in descending inhibitory pathways, combined with an increased or no change in response in descending facilitatory pathways,
such as that more pain related activity ascends but without a compensatory rise in descending pain inhibition or decline in pain facilitation. This is clinically detectable as increased
pain sensitivity and widespread hyperalgesia.
230 J.H. Bourke et al. / Journal of Psychosomatic Research 78 (2015) 228–236

there is an overlap in the pathways involved in spinal and supraspinal These manifestations of CNS sensitisation can be assessed using
mechanisms of pain perception (see Fig. 1a and b). quantitative sensory testing (QST). QST is a well-validated research
tool involving psychophysical methods that systematically document
alterations and reorganization of nervous system function and, in
Spinal sensitisation particular, of the nociceptive system [37]. As such, QST provides insights
into underlying pain mechanisms and is able to identify central nervous
Spinal sensitisation may follow the activation of nociceptive path- system sensitisation [38,39]. The most commonly applied tests are
ways by peripheral injury, such as that caused by trauma or inflamma- measures of enhanced temporal summation, widespread hyperalgesia
tion, resulting in the release of substance P and pro-inflammatory and conditioned pain modulation (CPM). It is beyond the scope of this
cytokines [24] and the activation of spinal cord glial cells [25]. In turn, article to detail the execution of these tests and their various modalities,
this may result in the increased release of glutamate [26] and the which have been reviewed in detail elsewhere [37]. Although QST is
long-term potentiation of such changes at the level of the dorsal horn. able to discriminate between CS and non-CS, it is generally accepted
This dorsal horn sensitisation causes the ‘gate’ to spinal pain pathways that QST is a measure of predominantly spinal mechanisms, albeit that
to remain open even without further noxious stimulation. This effect these are influenced supraspinally by higher cortical centres and so
is accentuated by a reduction in descending inhibition that would ordi- does not exclude the possibility of further modulation. Furthermore,
narily dampen the sensation of pain [27]. The overall effect is to gener- the utility of QST in detecting CS is determined, in part, by the battery
ate a state of increased activity in ascending (activating) pathways and a of tests employed with some providing insufficient evidence for a
reduction in activity in descending (inhibitory) pathways. The resultant sensitised state when used in isolation [40].
hypersensitivity is clinically evident as increased sensitivity to painful
(hyperalgesia) and non-painful (allodynia) stimuli (see Fig. 1a & Central augmentation of the neural network
b) [15,28]. The loss of descending inhibition also means that the normal
process by which the spread of pain is inhibited is lost, resulting in both During the normal perception of pain, the sensory, evaluative and
secondary hyperalgesia (hypersensitivity in neighbouring derma- affective attributes of a stimulus are applied by a network of higher
tomes) and widespread hyperalgesia (hypersensitivity at remote brain centres [20]. In CS, this neural network becomes hyper-
sites). When combined with increased ascending pathway activity, responsive. Each region of this network, or combinations thereof,
this results in the slow summation of stimuli, with stimuli of the same serve different functions in the experience of pain [41] which, when
intensity becoming more painful (enhanced temporal summation or combined, contribute to different aspects of the experience of pain,
wind-up) [29,30]. These phenomena have been demonstrated in a vari- such as unpleasantness. One such subdivision provides a triumvirate
ety of FSS, including IBS [31,32], fibromyalgia [33,34] and CFS [35,36] made up of lateral (sensory and discriminative), medial (affective and
(see Table 2). motivational) and frontal (cognitive and evaluative) systems [41,42].
The relative contribution of these components to the pain experience
Table 2 may vary between individuals and pain disorders, potentially contribut-
Support for central sensitisation in functional somatic syndromes. ing to whether a chronic pain disorder develops, the nature of that
disorder, and possibly the individual variance in the experience of
Spinal sensitisation: IBS [31,32]
temporal summation, FM [33,34] pain. This is important in understanding how chronic pain differs from
widespread hyperalgesia CFS [35,36] acute pain, with the focus being more on the sensory component in
and allodynia TMJD [63,64] acute pain, and the motivational and evaluative systems being
Tension-type headaches [65] predominant in chronic pain. This neural network therefore
Idiopathic lower back pain [66]
Vulvodynia and chronic pelvic pain [67]
demonstrates a multimodal response to nociceptive, somatosensory,
Interstitial cystitis [68] auditory and visual stimuli [43]. Furthermore, these responses are
Central augmentation of the neural IBS [69] more dependent on novelty and context than the nature or modality
network that contributes to the FM [70] of the stimulus [43].
perception of pain CFS [71]
Augmented responses to painful stimuli have been shown in several
TMJD [72]
Idiopathic lower back pain [66] different FSS (see Table 2) and the concept of multimodality is evident
Chronic pelvic pain [73] in these conditions. For example, in both FM [44] and CFS [45], neuroim-
Response of pain to centrally Antidepressants: TCAs [74], SNRIs [75,76] aging studies have shown increased neural recruitment (as demonstrat-
acting agents Antipsychotics: quetiapine [77], ed by increased regional activation) with cognitive tasks, reflecting a
amisulpride [78]
Alpha 2 delta ligands: pregabalin [79],
centrally mediated state of multimodal hyper-responsivity, whilst in
gabapentin [80] FM, low thresholds to auditory tones correlate with pressure pain
Cognitive–emotional processes MDD [174] thresholds suggesting that these are in part due to a shared variance be-
common to the FSS and associated Somatisation [175] tween pressure pain and auditory thresholds [46].
with amplification and extension Catastrophising [176]
The insula and striatum are two of the most commonly identified
of pain Fear avoidance [177,178]
Kinesiophobia [179] components of the neural network activated by pain and contribute to
Autonomic nervous system IBS [159] the affective/motivational and sensory/discriminative subsystems of
dysregulation FM [158,161] this network. The insula appears to act as the integration centre for mul-
CFS [160,163] timodal inputs involved in pain [47], interoception [48], threat detection
Sleep disruption IBS [127,131]
associated with bodily arousal [49], emotional regulation [50] and
FM [136,140]
CFS [135] motivational salience in learning models [51]. The integration of this
Neuroendocrine dysregulation IBS [156,157,180,181] information enables the insula to serve as a site for comparison between
FM [86,149,150,155,156,182–184] expected and perceived sensory mismatches (‘mismatch negativity’),
CFS [87,89,155,164,184,185]
that in turn allows for accurate self-monitoring and the preferential
Idiopathic lower back pain [183]
Chronic pelvic pain [186] processing of salient (important) sensory information [52].
Salience does not refer to the attributes of a given stimulus alone but
Abbreviations: FSS — functional somatic syndromes; IBS — irritable bowel syndrome;
FM — fibromyalgia; CFS — chronic fatigue syndrome; TMJD — temporomandibular joint
rather their comparison with those of surrounding stimuli and the
disorder; TCAs — tricyclic antidepressants; SNRIs — serotonin noradrenaline reuptake ability of a stimulus to stand out from others [53]. The salience of a
inhibitors; and MDD — major depressive disorder. stimulus is dependent upon speed of onset [54], novelty [55], context
 J.H. Bourke et al. / Journal of Psychosomatic Research 78 (2015) 228–236 231

and past experience [56] and its application is a function of part of the association between adverse childhood experiences with
neural network that responds to pain — the ventral striatum [57]. The hypocortisolism in FSS and chronic pain [87,88]. HPA axis involvement
detection of salience allows for the assessment of mismatch negativity has been implicated by nucleotide polymorphisms in sub-groups of
based upon prior exposure [56], which in turn facilitates attentional CFS [89], which supports its role in predisposition or cause rather than
processing and response generation [58]. Both the application and effect of these disorders. Such a mechanism may affect the conse-
recognition of salience are therefore a vital part of threat detection quences of events experienced as an adult, such as a precipitating infec-
essential to an organism's survival [59]. Nociception is vital for threat tion or other stressors. The biological mechanism involved appears
detection, representing the most proximal and dangerous of threats; related to centrally sensitising phenomena, with early adversity being
nociceptive stimuli are consequently highly salient. Given that the associated with neuroendocrine sensitisation [87], limbic system
neural network activated by pain is also involved in threat detection hyper-responsiveness and reduced hippocampal volumes [90]. These
and that it can be influenced by context and novelty, it has been may be governed by epigenetic changes [91,92] and not only confer sus-
proposed that this system's primary role is in salience detection and ceptibility to infections or their immune response, but also to stress re-
threat appraisal [43,60]. lated illnesses such as affective disorders and the FSS [87,93].
The initial processing of salience may occur as early as the spinal
cord; peripheral nociceptors respond preferentially to highly salient Genetic contributions to functional somatic syndromes and
stimuli [61], including pain. This detection of salience is facilitated by central sensitisation
mechanisms of descending inhibition, responsible for the suppression
of less relevant stimuli, so that only the most salient information is proc- A genetic predisposition may exist for the FSS (e.g. FM [94]), which is
essed within this neural network. When this mechanism fails, such as in independent from the mood disorders that frequently co-occur. The
spinal sensitisation, non-salient information is processed to the same Swedish twin studies [82,95,96] examined the symptom profile in
extent as salient information, generating an attentional bias towards over 30,000 identical twins for latent traits in CFS, FM, IBS, recurrent
ordinarily non-salient stimuli and resulting in sensory amplification headache, major depressive disorder and generalised anxiety disorder.
[62]. In short, the combination of spinal and supraspinal mechanisms Two vulnerabilities were reported for the development of FSS; one
involved in CS allows the processing of all information as salient, with was more heritable and related to the development of a mood and
threat detection becoming unfiltered with a near-permanent state of anxiety disorders, whilst the other was acquired and specific to the
response readiness. In turn, this would have a direct effect upon higher particular FSS developed. This overlap has been noted in other studies
cortical areas responsible for the assessment of both mismatch negativ- of chronic disorders of idiopathic pain [97]. These data suggest that
ity and response prediction as all stimuli may generate a greater activa- genes may “lump” these disorders together, whilst environmental influ-
tion and response, than would be predicted based upon prior ences split them apart into their individual syndromes.
experience of a similar context. Sensitivity to pain of itself may be a heritable trait [98]. Specifically,
In the context of the FSS, therefore, an explanation for the disparity catecholamine-O-methyl transferase (COMT) val/met polymorphisms
between stimulus and perception, and the lower thresholds for stimulus may explain individual differences in sensitivity to pain [99]. The associ-
tolerance in multiple modalities typical of these disorders, is related to ation between COMT polymorphisms and neural network activation in
the following: a loss of censorship of peripheral nociceptors, afferent response to painful stimuli correlates with the stimulus intensity
messages at the level of the spinal cord, an increase in mismatch nega- required to induce a constant pain sensation [100]. COMT polymor-
tivity, and the application of salience and threat detection at the level of phisms define low, average and high pain sensitive groups and the
the neural network. high sensitivity group is more likely to develop chronic disorders of
idiopathic pain [101]. COMT is also influenced by oestrogen. Oestrogen
Central sensitisation in the functional somatic syndromes receptor density is high in brain areas involved in pain perception
[102] and in women, pain sensitivity varies during the menstrual cycle
Evidence for CS in the FSS is growing (Table 2) [13], from various with lower pain thresholds being present during the luteal phase
different forms of investigation, including QST [31–36,63–68] and [103]. This may provide part of the explanation firstly, for the sex differ-
functional neuroimaging [66,69–73]. Further support comes from the ences seen in these conditions, where there is typically a female
successful use of centrally acting agents to treat the disorders [74–80], predominance and secondly, for the symptom exacerbation seen in
implying the stabilisation of dysregulated CNS mechanisms (Table 2). some disorders during menstruation (e.g. IBS [104]).
However, not all FSS demonstrate sensitisation to all modalities of CS, or susceptibility to it, also demonstrates heritability; both sec-
stimuli [81]. This variation might suggest heterogeneity amongst FSS; ondary hyperalgesia and allodynia are heritable with an estimated
it is potentially explained by the fact that standardised protocols are 50% genetic contribution to the pain variance [105]. This is supported
often lacking, making comparisons between the individual FSS difficult. by animal models suggesting a genetic contribution to central sensitisa-
In particular, the majority of earlier studies in this area have relied on tion through hypersensitivity to calcitonin gene-related peptide [106].
tests of temporal summation alone to assess for the presence of CS. These heritability studies are yet to be applied to the FSS.
Although the facilitated degree of temporal summation indicates an Is CS the cause or effect of FSS? Thermal and ischaemic stimuli and
enhanced central integrative mechanism (i.e. CS) [30], this may be tolerance to temporal summation, in asymptomatic individuals, in
insufficient to adequately distinguish between CS and non-CS when conjunction with measurement of the three COMT haplotypes (incorpo-
used in isolation [40] rather than, for example, in combination with an rating low, average and high pain sensitivities) can predict the subse-
assessment of descending inhibition such as CPM. quent onset of temporomandibular joint dysfunction [101]. This
would not only suggest that CS predates the onset of FSS but also that
Central sensitisation and risk factors for functional somatic syndromes it can be used to predict the onset of FSS, in combination with COMT
analysis. COMT polymorphisms therefore may provide a link between
A variety of environmental and psychosocial factors are recognised CS, the neural network involved in the perception of pain, and the FSS.
as risks for FSS [82]. These include childhood adversity and personality However, although COMT polymorphisms have been associated with
traits as predisposing factors, and physical trauma and infections as IBS, including specific IBS related bowel patterns [107], evidence is
triggers [83]. Any kind of early life adversity is more commonly reported weaker for FM [108] and CFS [109]. Negative findings here may further
in all the FSS [10,11,84], although this association may vary across FSS reflect the heterogeneity of these conditions [110] resulting in a dilution
[85]. This predisposition may be governed by the effects of such events effect, as has been demonstrated in CFS through latent class analysis and
on the neuroendocrine stress axis [86], as demonstrated by the genetic evaluation of monoamine oxidase and HPA-related genes [89].
232 J.H. Bourke et al. / Journal of Psychosomatic Research 78 (2015) 228–236

Central sensitisation as an explanation of non-painful symptoms and depressive symptoms and disability in FSS [140]. Experimental sleep
comorbidities in functional somatic syndromes deprivation has been used to reduce pain thresholds, with these only
returning to baseline with a restoration of SWS [141]. SWS disruption
Comorbid psychiatric disorders and pain perception also interferes with the normal CNS inhibitory responses to painful
Comorbid mood disorders are more likely in those with FSS nociception in healthy subjects [142], resulting in a hypersensitive
compared to those without [111]. Susceptibility to major depressive state resembling CS [143].
disorder (MDD) and anxiety disorders is a known risk marker for the During sleep, the brain does not discriminate between sensory
development of FSS [112]. The difficulty here is that a previous mood inputs, which require consciousness to translate them into an emotional
disorder may represent the risk of developing a FSS when accompanied and physiological experience, but it remains ‘aware’ of and reacts to
by a comorbid mood disorder, rather than being specific for a FSS alone threatening stimuli [144]. This allows a ‘threat detection’ system to re-
[113]. The risk might be related to abnormal central processing leading main active, but prevents awakening due to irrelevant stimuli. That is
to both mood disorders and FSS. This would seem feasible, with their to say that highly salient stimuli, including pain [144], are still able to
shared neuroanatomical and neurobiological substrates [114]. promote arousal. Arousals are detectable as transient rises in autonomic
Pain perception in MDD is mostly increased [115,116], but decreased nervous system (ANS) activity, already demonstrated in some FSS [110,
[117] and normal pain thresholds have also been demonstrated [114, 145]. These are able to activate low intensity responses, which typically
117]. The use of non-standardised protocols may have made the results remain unconscious, but may result in motor restlessness. CS results in a
incomparable. A more recent study [118] using standardised QST in multi-sensory hyper-responsivity in the neural network, responsible for
depressive disorder without painful symptoms, as compared with FM, multimodal threat detection. During sleep, the CNS is arousable by
found a reduced threshold to cold and increased temporal summation threatening, highly salient stimuli that promote wakefulness. This
in depressive disorder, suggesting that CS is a factor in pain perception threat detection system is less discriminate in CS and so mini-arousals
in depression. The study sample included many subtypes of ‘depres- may be more frequent, resulting in poorer sleep, more symptoms and
sion’, including adjustment disorder, and the presence of enhanced greater disability [140]. The connection here may be substance P,
temporal summation alone to determine CS is debated [40]. which is raised in these disorders [146,147]. Its role in pain is well
Chronic pain is a common symptom in post-traumatic stress disor- known, however animal models have also implicated its involvement
der (PTSD) [119], with sufferers often also having FM [120]. PTSD and in sleep disturbance [148]. This suggests that NRS may be a consequence
chronic pain may share cognitive and emotional risk markers. One of CS, rather than a factor that maintains it.
such example is ‘anxiety sensitivity’ [121], which is thought to amplify
both the intensity of emotional reactions and sensitivity to pain [121].
PTSD patients paradoxically appear hyper-responsive to suprathreshold Neuroendocrine axis dysregulation
noxious stimuli (i.e. they rated them as being more intense than did Disturbed sleep/wake functions are closely associated with dysregu-
healthy controls or those with other anxiety disorders) but were lated circadian rhythms, such as those of the tubero-infundibular and
hyposensitive to noxious stimuli with higher thresholds for rating HPA axes. Growth Hormone (GH) is released at the onset of SWS; wak-
these stimuli as painful [119]. These authors suggest that hyper- ing halts its secretion and part of its function is cell growth and repair.
responsiveness may be mediated by anxiety and hyposensitivity medi- This not only ties GH to abnormalities of sleep but also, through disrup-
ated by dissociation, sometimes found in PTSD [122]. Temporal summa- tion of normal healing and repair, to enhanced pain, muscle fatigue and
tion was normal, leading the authors to conclude that altered pain the daytime consequences of NRS [133]. Reduced GH secretion has been
sensitivity in PTSD cannot be simply due to CS [123], although this demonstrated in FM [149], with one study suggesting that GH is an
conclusion is provisional being based solely on temporal summation. effective treatment [150]. Thus, through a centrally sensitised disrup-
The experience of peritraumatic pain and the early provision of tion of SWS, dysregulation of neuroendocrine function is also implicated
adequate analgesia are important factors in determining PTSD [124, in CS.
125]; these factors may need to be separated in the examination of HPA axis involvement has been implicated in sleep abnormalities
central pain processing in PTSD. [151] and at a genetic level in FSS [89], whilst hypocortisolism resulting
from childhood adversity may increase vulnerability to FSS [87,152].
Sleep disturbance in functional somatic syndromes and Cortisol has pain-inhibiting effects, whilst corticotrophin releasing
central sensitisation factor (CRF) also leads to the release of β-endorphin, explaining in
Subjective reports of sleep difficulties are common in all FSS part the role of this hormone and releasing factor in pain sensitivity
[126–128], even when other causes of poor sleep such as comorbid [153,154]. However, reports of HPA axis dysfunction vary between
depression and anxiety are controlled for [129]. In particular, sleep is FSS, with a recent meta-analysis reporting hypocortisolism in CFS and
described as being non-refreshing, with consequent fatigue, daytime in women only with fibromyalgia but normal cortisol levels in IBS
somnolence, irritability, word finding difficulties, poor short-term [155]. This may reflect either methodological heterogeneity or the
memory in addition to physical symptoms [130], including effects on heterogeneity of FSS. However, the HPA axis is closely regulated
bowel function [131] as well as being strongly associated with chronic through negative feedback mechanisms and the neuroendocrine state
pain, as discussed below. Non-restorative sleep (NRS) implies self- in the chronic phase of illness does not necessarily reflect its status at
reported restlessness or poor quality sleep [132]. Studies looking at onset. Some have suggested that there exists a greater rise in cortisol
different components of insomnia, such as NRS, difficulty initiating response to acute stress in IBS, on a background of normal or low base-
(early insomnia) or maintaining sleep (middle insomnia) have line cortisol, and reduced or raised adrenocorticotrophic hormone
suggested that NRS is more likely to be coupled with daytime problems (ACTH), whilst in CFS and FM, delays in the decline in cortisol after
than early or middle insomnia [133]. the experience of stress have been reported on a background of reduced
Sleep studies suggest that increased alpha activity (light sleep) ACTH [156]. This might infer abnormalities in corticotropin releasing
during slow wave (deep) sleep (SWS) induces NRS, commonly referred hormone (CRH) release — relevant to exacerbations in pain [153,154]
to as alpha–delta sleep [134], which has been demonstrated in FSS [135, in response to stress in FSS but also to other symptoms such as those
136]. These alpha waves are conceived of as ‘mini arousals’ that are affecting the bowel, where intestinal permeability increases in response
responsible for the consequences of NRS. The subjective report of poor to CRH release [157].
sleep correlates with unexpected alpha activity [136]. Dysregulated tubero-infundibular and HPA axes may therefore be
Experimental disruption of SWS has also been shown to induce pain associated with CS in FSS through disruption of sleep and enhanced
and fatigue in healthy volunteers [137–139] and this also increases pain, pain in addition to other symptoms, including bowel dysfunction.
 J.H. Bourke et al. / Journal of Psychosomatic Research 78 (2015) 228–236 233

Although the direction of HPA axis abnormalities and their location in Table 3
the feedback loop are yet to be adequately determined. Criteria that biomarkers should fulfil in order to be considered as endophenotypes [169,170].

Association with illness or disorder within the population

Autonomic dysregulation Demonstrates heritability
Autonomic dysregulation (underactivity in the parasympathetic Demonstrates state-dependence (i.e. present irrespective of active illness or disorder)
Co-segregation with illness within families
nervous system and/or sympathetic overactivity) has been implicated
Found in unaffected family members more frequently than the general population
in the FSS by demonstration of reduced heart rate variability during
sleep and when awake [158–160] and may contribute to symptoms
such as sleep disturbance and fatigue [161]. The autonomic nervous
system (ANS) may be associated with abnormal stress responses and syndromes has been unfruitful — vulnerability to the development of
contribute to pain. This may be either an initiating or maintaining factor FSS may be marked by CS, whereas precipitating events such as envi-
in the central augmentation of the neural network responding to pain, ronmental exposures might thereafter mark the development of specif-
notably the insula [162], in centrally sensitised individuals. ic syndromes or their sub-phenotypes. In short, this endophenotype
might suggest that we should lump first, then split afterwards.
Fatigue
Fatigue is a ubiquitous symptom in FSS. As a chronic symptom, it
resembles pain in so far as that it is not a unitary phenomenon but likely Future research
reflects the involvement of multidimensional processes, irrespective of
the FSS in which it arises. Fatigue is associated with disruptions of Future work will need to adopt an integrated, biopsychosocial
SWS [138], ANS dysfunction [163], neuroendocrine dysregulation approach and focus on both further case control and prospective studies
[164], including genetic polymorphisms [89], as well as with CS [14, of CS, measured in different modalities, in different FSS, including family
165]. Evidence to date increasingly suggests that as a symptom of FSS and twin-studies, and particularly test the persistence of CS during re-
it is associated with CS [14]. mission of these disorders, in order to see whether this endophenotype
is state or trait related. Prospective studies might involve seeking asso-
Central sensitisation as a vulnerability endophenotype for the functional ciations with both childhood adversity, the relationship with physiolog-
somatic syndromes ical stress responses and exposure to environmental precipitating
factors, regressed against the development of CS and subsequent evolu-
The component parts of CS have been demonstrated in the FSS tion of FSS. Given the variability of results from genetic studies to date, it
(Table 2) and suggest that CS may represent an underlying vulnerable may be that polymorphisms are associated with a susceptibility to the
pathophysiology for FSS in general. By way of its effects on sleep, neuro- development of CS, to the development of an individual FSS, or to both.
endocrine axes and the ANS, CS may provide the physiological basis for Standardised QST protocols will be needed with appropriate control
symptoms other than pain in FSS. Furthermore, although further work is for the multitude of psychophysical variables that are present in the FSS,
required in those that recover from FSS, CS in FSS appears to be a which are known to independently affect pain perception (e.g. mood
constant state. This is important, as CS has been demonstrated in and sleep), and these will need to be combined with robust functional
other disorders, the pathophysiology of which has been more clearly neuroimaging studies in order to fully define the neurophysiology
defined. Two prominent examples are migraine and osteoarthritis of these syndromes and the relative contributions of supra- and sub-
[166,167]. As such, CS would not seem to be sufficiently specific to tentorial components to the final experience of pain.
FSS. However, in both migraine and osteoarthritis, CS seems to be an
induced and as such a temporary state. In migraine, 79% of sufferers
have been reported to demonstrate allodynia, predominantly ipsilateral Clinical implications
to the migrainous head pain during an attack, with no sufferers demon-
strating allodynia between attacks [166]. As such, CS in migraine seems The gradual emergence of neural correlates and biological mecha-
dependent upon the presence of active pathophysiology. In osteoarthri- nisms for functional somatic syndromes has the potential to alter not
tis, CS appears to return to a non-centrally sensitised state after success- only our understanding but also the nomenclature by which we define
ful surgical replacement of the affected joint and elimination of the our understanding. Terms such as psychosomatic, ‘medically unex-
osteoarthritis pain [167]. This would suggest that CS in osteoarthritis plained’, somatisation and somatoform seem to beg more questions
is an effect rather than a cause. Currently it is therefore unclear as to than answers, and have lost their clinical and scientific utility [172],
whether an ‘over-processed’ input in the periphery is required for a resulting in significant recent debate surrounding new classifications
centrally sensitised state to prevail. Data from osteoarthritis patients [5,173]. Perhaps more importantly, central sensitisation provides
[167] might suggest that this is essential and that CS can be reversed healthcare professionals with a model of understanding that can be
with the removal of this input. However, in FSS it is potentially possible readily shared with and understood by patients, which moves us on
that normal pathways exist to the level of the brainstem (by way of from the sterile and sometimes pejorative language of the past. It has
example) and that it is the supraspinal networks that are dysfunctional, the ability to define not only a better understanding of these most
without the need for an over-processed peripheral input. In turn, this difficult and complex disorders but also, through a clearer understand-
might allow for a concept of central augmentation of higher brain ing of their pathophysiological basis, how they might be better treated.
centres that is autonomous and independent of peripheral input — a In short, it may help to render the medically unexplained, explicable.
central rather than peripheral over-processing. Further work is required
in this area in order to elucidate the final contribution of supra versus
subtentorial components to the experience of pain. Conflict of interest
Therefore, in approaching the FSS as disorders united by CS with
different phenotypes determined by triggering environmental expo- Dr. Bourke has no conflicts of interest to declare. Professor Langford
sures, CS may represent a feasible endophenotype for these syndromes has been a speaker and provided consultancy for Grünenthal GmbH,
(Table 3) [14,168–170]. In this respect, further support exists in that CS Janssen-Cilag and Pfizer and has received departmental research grants
is manifested in both those with and without FSS, being more common and contract research income from Mundipharma and Grünenthal
in unaffected family members of those with FSS [171]. This would also GmbH. Professor White has done voluntary and paid consultancy
explain why the search for biomarkers specific to the individual work for the United Kingdom government and a reinsurance company.
234 J.H. Bourke et al. / Journal of Psychosomatic Research 78 (2015) 228–236

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