Source: Clinical Psychology Review
        Vol. 27, #7, pp. 781-797
Date:   October 2007
URL:    http://www.sciencedirect.com/science/journal/02727358


The cognitive behavioural model of medically unexplained symptoms: A
theoretical and empirical review
--------------------------------------------------------------------
V. Deary (a,*), T. Chalder(b), M. Sharpe(c)
a Institute of Health and Society, University of Newcastle, 21 Claremont Place,
  Newcastle Upon Tyne NE2 4AA, UK
b Cognitive Behavioural Therapy Institute of Psychiatry, Department of
  Psychological Medicine, Cutcombe Road, London SE59RJ, UK
c Psychological Medicine and Symptoms Research School of Molecular and Clinical
  Medicine, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital,
  Morningside Park, Edinburgh EH10 5HF, UK
* Corresponding author. E-mail address: vincent.deary@ncl.ac.uk (V. Deary).


Received 16 February 2006;
received in revised form 21 June 2006;
accepted 13 July 2006


Abstract

The article is a narrative review of the theoretical standing and empirical
evidence for the cognitive behavioural model of medically unexplained
symptoms (MUS) in general and for chronic fatigue syndrome (CFS) and
irritable bowel syndrome (IBS) in particular. A literature search of Medline
and Psychinfo from 1966 to the present day was conducted using MUS and
related terms as search terms. All relevant articles were reviewed. The
search was then limited in stages, by cognitive behavioural therapy (CBT),
condition, treatment and type of trial. Evidence was found for genetic,
neurological, psychophysiological, immunological, personality, attentional,
attributional, affective, behavioural, social and inter-personal factors in
the onset and maintenance of MUS. The evidence for the contribution of
individual factors, and their autopoietic interaction in MUS (as hypothesised
by the cognitive behavioural model) is examined. The evidence from the
treatment trials of cognitive behavioural therapy for MUS, CFS and IBS is
reviewed as an experimental test of the cognitive behavioural models. We
conclude that a broadly conceptualized cognitive behavioural model of MUS
suggests a novel and plausible mechanism of symptom generation and has
heuristic value. We offer suggestions for further research.


1. Introduction: defining terms

"The term medically unexplained symptoms names a predicament, not a specific
disorder" wrote Kirmayer, Groleau, Looper, and Dao (2004). In the papers we
have reviewed it is used in three overlapping ways: (a) to refer to the
occurrence of symptoms in the absence of obvious pathology; (b) to refer to
individual clinical syndromes such as chronic fatigue syndrome (CFS) and
irritable bowel syndrome (IBS); (c) to refer to a subset of the DSM-IV
somatoform disorders category. Whilst classification remains disputed (for
details see the Introduction to this special issue), there is consensus that
a cognitive behavioural therapy (CBT) approach offers a useful explanatory
model of MUS (Neimark, Caroff, & Stinnett, 2005; Mai, 2004) and an effective
treatment (Kroneke & Swindle, 2000; Raine et al., 2002). These recent reviews
have validated the efficacy of CBT, but there has been less focus on the
model on which these treatments are based. This narrative review will focus
primarily on the theoretical standing and empirical evidence for the CBT
model of MUS, and for the specific CBT models for IBS and CFS. We will then
summarise the evidence for its effectiveness as a treatment with a view to
how this evidence can contribute to our evaluation of the CBT models. Finally
we will suggest areas for further research and development.

For the purposes of our literature search we adopted a broad definition of
MUS. We used MUS to refer to itself as a term ("medically unexplained
symptoms"), to individual syndromes and to some of the subcategories of
somatoform disorder. From somatoform disorders we excluded hypochondriasis,
conversion, pain and body dysmorphic disorders. Of the individual syndromes
we looked specifically at IBS and CFS. Pain was largely excluded because the
scope of the literature would have made the review unwieldy. In addition to
the aforementioned subcategories and disorders, we employed the search terms:
functional symptoms; functional syndromes; functional illness; functional
somatic symptoms; functional somatic syndromes; functional somatic illness
and medically unexplained illness. Searches were made of Psychinfo and
Medline from 1966 to the present and the Cochrane database. As a first
analytic step, we reviewed all the abstracts and reports obtained by using
"Medically (near) Unexplained (near) Symptoms" as a search term. We then
cross-referenced this and all the above terms with cognitive therapy;
behavio(u)r(al) therapy and cognitive behavio(u)r(al). All abstracts were
reviewed and this material was used to conduct the narrative review of the
CBT model of MUS which forms the bulk of this paper (Sections 2-4). The
search was then further limited to meta- analyses, clinical trials,
randomised trials, randomised control trials and controlled clinical trials.
This review of the clinical trials was performed with particular regard as to
how this body of evidence contributed to our understanding of the model
(Section 5). Relevant citations from papers identified were followed up and
colleagues were asked to identify any other relevant sources.


2. The model

Historically, the classical CBT model of emotional distress as proposed by
Beck distinguished between its developmental predispositions and
precipitants, and its perpetuating cognitive, behavioural, affective and
physiological factors (Beck, 1976). The CBT model of MUS retains this general
structure and its "three Ps": predisposing, precipitating and perpetuating
factors (see for instance Sharpe, 1995; Suraway, Hackmann, Hawton, & Sharpe,
1995; Richardson & Engel, 2004; Hutton, 2005). Treatment tends to initially
focus on the perpetuating cycle, attempting to dismantle the self maintaining
interlock of cognitive, behavioural and physiological responses hypothesised
to perpetuate the symptoms. The approach is very similar to Lang, Melamed,
and Hart's (1970) three system model of fear maintenance and desensitisation.
The sine qua non of any CBT model is a vicious circle, the hypothesis that a
self perpetuating interaction between different domains maintains symptoms,
distress and disability. Irrespective of the symptom type (as Allen, Escobar,
Lehrer, Gara, & Woolfolk, 2002, noted, none of the theories are organ
specific), the CBT models of MUS, IBS and CFS propose a model of perpetuation
that is, to borrow a term from systems theory and cell biology, autopoietic.

"Autopoiesis: the process whereby an organization produces itself. An
autopoietic organization is an autonomous and self-maintaining unity... The
components, through their interaction, generate recursively the same network
of processes which produced them" Valera (2005).

The CBT model of perpetuation differs from a more generic biopsychosocial
model (see Wade & Halligan, 2004) by proposing a unique autopoietic
interaction of cognitive, behavioural and physiological factors for each
individual. This model is essentially a hypothesis of a novel mechanism for
the generation of physical symptoms in the absence of physical pathology or
psychopathology. Several of the papers reviewed here propose such an
autopoietic model of symptom perpetuation (Barsky & Borus, 1999; Kolk,
Hanewald, Schagen, & Gijsbers van Wijk, 2003; Brown, 2004; Kirmayer et al.,
2004; Richardson & Engel, 2004; Rief & Barsky, 2005; Ursin, 2005). All assume
that symptoms are generated or maintained not by one specific disease process
but by the interaction of factors in distinct domains. Whilst each of these
authors give different weights to different domains, some emphasising
cognitive process, others physiological, they have in common the implicit
notion that a multi-factorial autopoietic cycle lies at the heart of the
experience of symptoms. All models which propose such a process will be
considered, for the purposes of this review, as examples of the cognitive
behavioural model of MUS. In the following, we will first review evidence for
the involvement of processes in these separate domains and then turn to look
at evidence for their autopoietic interaction in MUS.


3. Components of the CBT model for medically unexplained symptoms

3.1. Predisposing factors

3.1.1. Genetics and early experience

This is one of the least researched parts of the model. There is some
evidence for a genetic influence in the development of both unexplained
fatigue and somatisation (Kendler et al., 1995; Farmer, Scourfield, Martin,
Cardno, & McGuffin, 1999; Hickie, Kirk, & Martin, 1999); however this could
simply reflect the expression of an inheritable predisposition to general
distress (see Section 3.1.2 below). There is also some evidence that certain
types of early childhood environment increase the risk of developing MUS.
Hotopf (2003) reported that childhood experience of paternal illness could be
a risk factor, and highlights the possibility that vicariously learned
illness behaviour could later serve to perpetuate symptoms (see also Hotopf,
Wilson-Jones, Mayou, Wadsworth, & Wessely, 2000). This may also explain
Fisher and Chalder's (2003) observation that adult CFS sufferers report their
parents as having been over- protective; there is some evidence for this
learned illness behaviour in IBS (Lackner, 2005). A number of researchers
have reported evidence that childhood adversity in the form of physical or
sexual abuse is a risk factor for MUS in general (Fiddler, Jackson, Kapur,
Wells, & Creed, 2004), IBS (Hazlett-Stevens, Craske, Mayer, Chang, &
Naliboff, 2003; Lackner, 2005), CFS (Taylor & Jason, 2001), fibromyalgia
(Walker et al., 1997) and somatisation disorder (Morrison, 1989). This may be
linked to the sensitisation mechanisms discussed below. The large scale
longitudinal studies that would allow for more robust conclusions are
lacking.


3.1.2. Neuroticism and somatopsychic distress

Neuroticism (N) as a personality trait refers to a stable life long tendency
to experience negative affect. Watson and Pennebaker (1989) suggested it be
seen not just as psychological trait but as a more general predisposition to
experience "somatopsychic distress." There is good evidence for the lifespan
stability of this trait, with a median stability co-efficient for N of at
least 0.6 (McCrae et al., 2000). There is also good evidence relating N to
both anxiety and depression (Matthews, Deary, & Whiteman, 2003); to
heightened reactivity to stressors (Bolger & Schilling, 1991); to increased
incidence of objectively measured negative life events (Magnus, Diener,
Fujita, & Pavot, 1993); and to poor prognosis in depression (Surtees &
Wainwright, 1996). It is also associated with increased incidence of physical
illnesses such as Asthma (Huovinen, Kaprio, & Koskenvuo, 2001); poorer
prognosis following Coronary Heart Disease (CHD) and increased risk of
cardiac events (Denollet & Van Heck, 2001); and with the occurrence of
multiple physical ailments such as CHD, hypertension and gastro-intestinal
illness (Matthews, Yousfi, Schmidt-Rathjens, & Amelang, 2002). N emerges from
this data as being an important predictor not of specific pathologies, but of
a generic vulnerability to physical illness and psychological distress.

Given the above it is hardly surprising to find that high N is also
associated with MUS. High N has been demonstrated in functional dysphonia
(Deary, Scott, & Wilson, 1997); in Irritable Bowel Syndrome (Hazlett-Stevens
et al., 2003); CFS (Deary, 2001); and in general MUS (Costa & McCrae , 1987;
Kirmayer, Robbins, & Paris, 1994; De Gucht, Fischler, & Heiser, 2004a; De
Gucht, Fischler, & Heiser, 2004b). The aspects of perfectionism associated
with CFS (White & Schweitzer, 2000; Deary, 2001) are the "negative" self
critical aspects which are also positively correlated to N. Neuroticism could
potentially provide a parsimonious explanation of diverse findings. For
instance, the genetic component of MUS could be partly explained by N, which
has a heritability of around 50% (Matthews et al., 2003). The consistently
high association between MUS, anxiety and depression could be a manifestation
of an underlying tendency to experience somatopsychic distress. Indeed in
their meta-analyses of several medically unexplained syndromes and their
associated levels of anxiety and depression, Henningsen, Zimmermann, and
Sattel (2003) reached just this conclusion (see below).

N is also associated with several mechanisms that the CBT model hypothesises
are involved in symptom perpetuation. It is correlated highly with
harm-avoidance (Cloninger, 1987); ease of response suggestibility and
conditioning to noxious stimuli, and increased generalisation of conditioned
response (Van den Bergh, Winters, Devriese, & Van Diest, 2002); increased
experience of physical symptoms post vaccination (Petrie, Moss-Morriss, Grey,
& Shaw, 2004); biased attention to somatic danger signals such as pain or
fear (Matthews et al., 2003); compromised immune functioning (Marsland,
Cohen, Rabin, & Manuck et al., 2001); increased incidence of negative life
events (Magnus et al., 1993; Kendler, Gardner, & Prescott, 2003); and a
heightened stress response to adverse life events (Bolger & Schilling, 1991).
All of the foregoing factors have been proposed as factors in the
precipitation or perpetuation of MUS. N, which is higher on average in
females than males, might also partly explain the female preponderance of
MUS, (see Van Diest et al., 2005, for a full discussion of this.).

Closely linked to this notion of a predisposing "distress proneness" are the
associations between MUS, anxiety and depression. Henningsen et al. (2003)
found that MUS are consistently positively correlated with high levels of
anxiety and depression. They concluded: "In our view, it is most parsimonious
to interpret the findings as implying that medically unexplained physical
symptoms are best described as constituting one dimension of common distress
symptoms and disorders alongside depression and anxiety" (p. 532).


3.2. Perpetuating factors

The CBT model proposes that cognitive and behavioural factors interact with
physical factors to produce symptoms (Lang et al., 1970). There has been much
promising work in recent years investigating mechanisms other than physical
pathology that might be partly responsible for perpetuating MUS.


3.2.1. Sensitisation

Sensitisation refers to the tendency to have a heightened response to stimuli
because of prior experience of them. For instance, in animals the prior
experience of stressful stimuli lead to increased physiological and
behavioural responses to future stressors, and to increased incidence of
physical pathology, particularly if the initial stressors were uncontrollable
and unpredictable (Overmier & Murison, 2005). Rygh et al. (2005) has studied
a specific sensitisation mechanism - long term potentiation (LTP) - in
humans. LTP can be induced in pain pathways by prior experience of pain or
noxious stimulation which lowers the threshold for future stimulation. Rygh
et al. (2005) suggested that central mechanisms such as vigilance and
attention, or the effects of anxiety, depression or stress, may dampen
inhibition of these pathways, lowering the threshold yet further. This could
lead to normally benign sensations being experienced as pain, leading in turn
to further sensitisation and vigilance. Here we have the rudiments of an
autopoietic mechanism maintaining the experience of pain. LTP also
illuminates other findings (e.g. Heim, Ehlert, Hanker, & Hellhammer, 1998)
that previous physical trauma leads to increased pain sensitivity. Rygh goes
so far as to speculate that in as much as LTP is the cellular substrate of
learning and memory, cognitive behavioural therapy works by changing synaptic
potentiation in the brain. There is limited evidence for such sensitisation
processes in IBS (see Lackner's (2005) review) and in fatigue patients
(Stubhaug, Tveito, Eriksen, & Ursin, 2005).


3.2.1.1. The HPA axis and sensitisation.

Physical and emotional stress in humans causes a hormonal cascade beginning
in the hypothalamus, passing to the pituitary and ending with the increased
production of cortisol from the adrenal cortex. Within this system - the
hypothalamus pituitary adrenal axis (HPA axis) - both positive and negative
feedback loops exist to regulate the body's response to acute and chronic
stress. The HPA axis alters energy metabolism, influences immune functioning
and affects both energy and mood with, for instance, high levels of cortisol
being consistently found in major depression. Low cortisol has been found in
patients with CFS (Roberts, Wessely, Chalder, Papadopoulus, & Cleare, 2004),
fibromyalgia and low back pain (Griep et al., 1998) and also in PTSD
(Rohleder, Joksimovic, Wolf, & Kirschbaum, 2004). One interpretation is that
prolonged activation has led to a "burnout" response and a down regulation of
HPA activity in these disorders. This down regulation may lower the threshold
for stress sensitivity.

Fries, Hesse, Hellhammer, and Hellhammer (2005) proposed a developmental
model along these lines: prolonged stress leads to HPA axis down regulation
and reduced cortisol production. This hypocortisolism is marked by a "symptom
triad" of pain, fatigue and stress sensitivity. Further, there are
indications that lowered cortisol could lead to increased release of
inflammatory cytokines, potentially important determinants of the "illness
response", characterised by lassitude and behavioural avoidance. Finally they
suggested that hypocortisolism may in fact be an adaptive response that
produces stress avoidance, energy conservation and physical recuperation.
Dantzer (2005) developed this hypothesis yet further, suggesting that there
are two kinds of stress response, one related to anxiety and the other to
depression (see also Maier & Watkins, 1998). The latter is the "recuperative
system" described above, associated with defensive withdrawal and reduced
activity. Dantzer suggested that this essentially adaptive system can become
triggered by more generic danger signals and stressors, and can become
sensitised to non-pathogenic input, in a way analogous to the fear response
in anxiety. He concluded that "all the necessary ingredients are there for a
renewed biopsychological approach to somatisation and somatoform disorders"
(p. 951).

Cleare (2004) has reviewed the evidence for HPA axis involvement in CFS.
Whilst there is evidence for an increased sensitivity to the negative
feedback effect of glucocorticoids in the HPA axis, and for reduced ACTH and
cortisol responses, there is no obvious HPA axis dysfunction. Rather a varied
picture of HPA axis alteration emerges which could have multiple
determinants, such as sleep dysregulation, stress, psychiatric co-morbidity
etc. Gaab et al. (2005) reported a similarly heterogeneous and inconclusive
picture. They suggested, from their research, that their may be "an enhanced
perception of cytokine-induced symptoms" possibly due to sensitisation of the
HPA axis.


3.2.2. Attention -- cognitive activation and behavioural inhibition

Rief and Barsky (2005) acknowledged Dantzer's research but noted that whilst
there is some evidence that immune changes can induce behaviour change, it is
"unclear whether this causality can also be bi-directional and whether it
contributes especially to the development and maintenance of somatoform
symptoms in humans." They observed that the biological findings in patients
with MUS are highly varied and do not yet present a consistent and coherent
picture. Whilst there is some evidence of increased autonomic arousal and of
delayed recovery of the stress response, these findings vary between
conditions and between different phases of the same condition. Therefore
rather than anchor their explanation to a particular bodily system, Rief and
Barsky (2005) proposed a more generic model in which symptoms arise through a
two stage process of generation and selection. At the first stage, bodily
symptoms may be generated by multiple determinants including over-arousal,
chronic stressors, HPA activity, sensitisation etc. At the second stage a
hypothetical filter system selects symptoms for conscious attention. This
selective process will in turn have multiple determinants: health anxiety,
depression, lack of distraction, uncertainty as to origin of symptom etc.
These contribute to "faulty filtering" and increased symptom perception.
Brown (2004) has suggested a similar model which emphasises the roles of
attention, mis-attribution and mis-interpretation in the maintenance of MUS.

It is to this "filter system" that we now turn. It is a notable observation
that of all the sensations constantly processed by our bodies, very few reach
our conscious attention. Most of the activity of our body is monitored and
orchestrated unconsciously by more or less automatic mechanisms. These form
the so-called "cognitive unconscious" which is the focus of the rapidly
growing body of psychological research and theory known as embodied
cognition. Shaun Gallagher's recent book (2005) presents an exhaustive survey
and synthesis of this new field of study. One of the key hypotheses of this
perspective is that conscious awareness plays very little part in our daily
activities. Mostly our body and its processes run on automatic and remain
experientially transparent, passing below the radar of attention. However
occasionally physiological or cognitive changes can bring to the foreground
processes and sensations that would normally escape notice. .... "Such
hyper-reflection can generate a body image that exaggerates proprioceptive
and kinaesthetic sensations, and interferes with the normal functioning of
the normally tacit body schema" (p. 205) (Gallagher, 2005).

It is precisely this kind of mechanism that has been suggested to be at work
in MUS in conjunction with the sensitisation processes described above. Ursin
(2005) noted that "cognitive bias is a higher form of sensitisation...
anxious people detect fear related stimuli at a lower threshold than normal
controls." Ursin's model is based on his notion of a Cognitive Activation
System (CAS) which, in response to threat or stress, produces a state of
arousal "which is sustained until the source of stress is eliminated" i.e.
until some instrumental action is taken to deal with the stressor. This model
is similar to Gray's (1991) Behavioural Inhibition System (BIS) which was
proposed to be specifically oriented to aversive, fearful and novel stimuli,
producing arousal, behavioural inhibition and selective attention to the
stimuli. In both models the first function of the system is to stop other
ongoing activity and to re- orientate attention to the
threat/stressor/symptom. The arousal, as well as enabling action, acts as a
motivational negative reinforcement: the person acts to reduce their aversive
state of arousal. These ideas may be of considerable relevance to our
understanding of MUS. Prolonged activation of the CAT/BIS could serve to
generate symptoms through the physiological processes described above (see
also Thayer, Pieper, & Brosschot, 2005). These symptoms in turn may become
novel aversive stimuli and thereby produce further arousal. Selective
attention is then directed to symptoms and to the thoughts associated with
them. A cognitive bias develops for symptoms, further amplifying them which
serves to further sensitise "the neural loops supporting cognitive
rumination... pain and illness lead to more pain and illness" (Ursin, 2005).
These models are notably similar to Barsky and Borus's (1999) somatosensory
amplification and Rief and Nanke's (1999) cognitive-psychobiological
framework.


3.2.2.1. Evidence for attentional processes.

The attentional models point to individual differences in attentional biases
with respect to threatening stimuli as a factor in MUS. The findings of
positive correlations between threat sensitivity, N, conditionability,
negative affectivity and MUS (MacCleod & Matthews, 1988; Derberry & Reed,
1994; De Gucht et al., 2004b; Petrie et al., 2004) are supportive of this
hypothesis. However is there any more direct evidence that attention is a
factor? Rief, Hiller, and Margraf (1998) have reviewed some of the literature
on cognition and attention. Whilst drawing the conclusion that attention is
an important variable, most of the studies linked attention to attribution.
Individuals who either perceived themselves as more vulnerable or the symptom
as more threatening were more likely to pay attention to the symptoms.
Experimentally, attention is a hard variable to isolate. There have been some
experimental tests (Pennebaker & Skelton, 1981; Barsky, Goodson, Lane, &
Cleary, 1988; Lautenbacher, Pauli, Zaudig, & Birbaumer, 1998) indicating that
distraction ameliorates and attention intensifies physical symptoms. Using
functional brain imaging Bantick et al. (2002) found that distraction did
decrease activity in pain related brain areas.

In CFS a recent trial found that the effect of treatment appeared partly to
be attributable to a decreased attention to the symptoms (Moss-Morris, Wash,
Tobin, & Baldi, 2005), whilst in IBS Lackner's (2005) review found some
evidence that cognitive processes, such as threat sensitivity, may influence
these visceral attentional processes, amplifying pain and normal sensation.

Overall, whilst attention seems to be important it has been hard to isolate
this process from attributions, unhelpful illness beliefs, medical
uncertainty and other factors which may serve to focus attention onto
symptoms. It is to this work that we now turn.


3.2.3. From attention to attribution and beliefs

Kolk et al. (2003) have, in an excellent review, attempted to marshal the
data on attention and attribution into a coherent model. Drawing on the work
of Pennebaker (1982), Cioffi (1991) and Kirmayer and Taillefer (1997), they
have suggested a Symptom Perception Model of MUS, in which negative
affectivity, selective attention and somatic attributions are hypothesised as
the key factors determining the experience of common physical symptoms.
Evidence for the model was obtained by Kolk et al. in a prospective test of
151 patients, one of few attempts to prospectively test a theoretical model
and hypothesised inter-relationships between variables.

Other research has studied the relationship of attribution to illness
behaviour and outcome (Sensky, MacLeod, & Rigby, 1996; Moss-Morris & Petrie,
2001; Kolk, Schagen, & Hanewald, 2004; Rief, Nanke, Emmerich, Bender, & Zech,
2004; Henningsen, Jakobsen, Shiltenwolf, & Weiss, 2005). There is a broad
consensus that making organic illness attributions, lack of normalising
attributions and high estimates of personal vulnerability predict increased
symptom experience and illness behaviours such as expression of symptoms and
seeking treatment, whereas psychological or mixed somatic and psychological
attributions predict better symptom outcomes. Those with more symptoms are
more likely to make mixed attributions. A tentative conclusion from the
research would be that it is the fixity and exclusivity of somatic
attribution, rather than just its type, which contributes to symptom
perpetuation.

Kirmayer et al. (2004) adopted a more qualitative approach to attribution and
looked at it from the viewpoint of illness narratives - how do people explain
symptoms to themselves? This approach is notable for eliciting multifaceted
attributions, with individuals from different cultures making sense of their
symptoms through complex narratives that involve social, emotional and
physical processes. A key finding from their work is that any narrative is
better than none; those who could not make sense of their symptoms in some
way were the most distressed, and reported the least benefit from the
interview process. Kirmayer's work highlighted what Henningsen et al. (2005)
also mention in their study: that is the paradox that much research on
attribution operationalises the mind/body dichotomy that is otherwise decried
by the researchers themselves. Patients are usually divided into
psychologisers or somatisers. Whilst patients who are multi-symptomatic tend
to make multi-factorial attributions, the current models tend to limit them
to just two often mutually exclusive styles. This cognitive bias on the
researchers part needs to be challenged in future research.

Illness attributions are often worked out with, or in spite of, the medical
profession, and several authors have looked at the part this interaction can
play in the development and maintenance of MUS. Simon, VonKorff, Piccinelli,
Fullerton, and Ormel (1999), Nimnuan, Hotopf, and Wessely (2000), Dowrick,
Ring, Humphries, and Salmon (2004), Gureje (2004) and Salmon, Dowrick, Ring,
and Humphries (2004) have all highlighted how a poor or absent relationship
with the general practitioner can lead to increased symptom reporting and
repeat consultations. Hotopf (2004) has compared the role of doctors in MUS
to that of parents of sick children. Both can reinforce unhelpful illness
behaviour and symptom interpretations.

Illness related beliefs have also emerged as potentially important factors in
the maintenance of symptoms. Deale, Chalder, and Wessely (1998) showed that
beliefs about the harmful effects of activity were related to poorer outcome
in CFS. The hypothesis from this is that the beliefs inform behaviour, in
this case activity avoidance, which in turn affects physiology and symptoms,
providing the rudiments of a vicious circle of symptom maintenance. The link
between beliefs and behaviour is further evinced in the IBS research
(Lackner, 2005) where catastrophic beliefs about symptoms have been shown to
contribute to behavioural avoidances and thus, potentially, anxiety and
symptom maintenance through operant conditioning. It is to the research on
behaviour that we now turn.


3.2.4. Response to illness

Several authors have observed that it is not just the illness, but one's
response to it that matters. For instance, Candy, Chalder, Cleare, Wessely,
and Hotopf (2004) reported that following glandular fever a graded return to
activity predicted a lower chance of developing CFS than rest. Hotopf, Noah,
and Wessely (1996) found that later fatigue was positively associated with
length of convalescence. In a similar study Spence, Moss-Morris, and Chalder
(2005) examined coping behaviour in 758 Campylobacter patients and found that
IBS at 6 months was associated with `all or nothing' coping behaviour at
baseline. As these authors have noted, there is actually relatively little
literature concerning illness responses, despite a clinically prevalent
belief that `all or nothing coping' and avoidance behaviours are important in
the onset and perpetuation of syndromes such as CFS. In chronic pain
avoidance has emerged as equally a potent predictor of disability as pain
(Rief & Nanke, 1999). More longitudinal work of this nature is needed to
clarify the role of behaviour in the development of MUS.

In the literature it is often difficult to disentangle the factors so far
presented: sensitisation, attention, attributions, beliefs and behaviour are
theoretically and experimentally difficult to isolate from each other as
distinct processes. Sensitisation may be linked to attention which may in
turn be informed by beliefs which may affect behaviour, and so on. As such
the research offers a kind of de facto support for the spirit of the CBT
model, which proposes precisely this sort of interaction. However failure to
experimentally isolate processes is not equivalent to evidence for their
interaction, and more work is needed on both individual factors and their
interaction before we can form more definite conclusions.


3.3. The straws that break the camel's back - precipitating factors

Finally we turn to the last link in the CBT model, the event or events that
are hypothesised as triggering the start of the self perpetuating cycle we
have sketched the evidence for above. The main topic that has been studied
here has been `life events'. This is a field too large to summarize
comprehensively, but we can address the key question ­ do life events
precipitate MUS ? - with a fairly unequivocal yes. Salit (1997), Chalder
(1998), Kroenke, Wood, Mangelsdorff, Meier, and Powell (1998), Theorell,
Blomvkist, Lindh, and Evengard (1999) have all reported that major life
events are more likely prior to the onset of CFS. Hatcher and House (2003)
investigated the role of life events further and repeated the finding that
they often precede onset, adding the observations that dilemmas ­ forced
choices between equally undesirable alternatives - appeared to be
particularly predictive. Life events have also been found to be important in
the onset of chronic pain (Craufurd, Creed, & Jayson, 1990) and IBS (Creed,
Craig, & Farmer, 1988). Again, neuroticism is a potential confounding factor
as Kendler et al. (2003) and Magnus et al. (1993) found that the occurrence
of objectively measured stressful life events are associated with
neuroticism.

The effects of life events may be to induce what has been called "prolonged
activation" i.e. chronic activation of the physiological stress responses
described in Section 3.2.1. The hypothesis is that activation of the stress
response over a period of time has neurological, endocrinological,
immunological and cardiovascular consequences. Brosschot, Pieper, and Thayer
(2005) pointed out that a key element of this process is "perseverative
cognition", that is worry or rumination, which serves to maintain the
physiological activation. Whilst the evidence for this mechanism is currently
patchy, what there is would fit the model so far presented, of an interaction
between environmental, physiological, behavioural and cognitive responses.


4. The coherence of the model

We have reviewed some of the cognitive, behavioural and physiological factors
that are thought to contribute to the onset and perpetuation of MUS. Overall,
the evidence reflects a welcome move from purely "psychological" models to a
more complex multifactorial approach. There is certainly evidence that
factors in each domain are associated with MUS. However, the key feature of
CBT model is that these individual components become locked into an
autopoietic cycle. It is intuitively obvious how this might happen. An innate
tendency to somatopsychic distress and ease of distress sensitisation,
combined with childhood adversity, increase both the amount of symptoms
experienced and lowers the threshold for their detection. Life events and
stress lead to physiological changes which produce more symptoms and set up
processes of sensitisation and selective attention. This further reduces the
threshold of symptom detection. Lack of explanation or advice increases
anxiety, symptoms and symptom focus. Stress cues become associated with
symptoms through classical conditioning. Avoidance of symptom provocation,
and symptom-led activity patterns, lead to further sensitisation through
operant conditioning. The prolonged stress of the illness experience itself
further activates physiological mechanisms, producing more symptoms,
sensitisation, selective attention and avoidance. The individual can thereby
become locked into a vicious cycle of symptom maintenance (see Fig. 1).

There are varying degrees of evidence for each of the components of this
model. What is lacking is solid proof of their interaction in vicious
circles, although all the models reviewed assume this interaction.

The CBT model of CFS (see Suraway et al., 1995; Deary & Chalder, 2006)
hypothesises that in vulnerable individuals, such as those who are
over-active or under-stress, CFS is precipitated by life events or viruses
leading to an autopoietic cycle in which physiological changes, illness
beliefs, reduced and inconsistent activity, sleep disturbance, distress,
medical uncertainty and lack of guidance interact to maintain symptoms. The
evidence supports some of the individual dots in this picture but not yet the
lines between them.

According to Lackner (2005), the CBT model of IBS (see Toner et al., 1998;
Hutton, 2005; Kennedy et al., 2005) has slightly more coherence and evidence
for it than the CFS model, and appears both less controversial and more
readily acceptable to patients. IBS perhaps benefits from being largely
localised to one organ system, where some of the interactions of
physiological and psychosocial processes are better conceptualised and more
widely accepted than the more diffuse, complex and idiosyncratic processes
that seem to be involved in CFS and general MUS.

What makes the CBT model so difficult to test may also be one of its chief
strengths: it is in many ways a meta- model, providing a skeleton structure
to join the dots of whatever factors each patient presents. Indeed factors
that are neither strictly cognitive nor behavioural, but have been found to
be important (for instance social support (Chalder, 1998) or benefit receipt
(Bentall, Powell, Nye, Edwards, & Richard, 2002)) can be incorporated into
this structure as perpetuating factors. This means that every client will
have, in effect, their own model, making the testing of a generic CBT MUS
model impossible. Rather, future testing of this model must be of individual
factors and of specified interactions between factors, such as HPA axis
activity, immune functioning and fatigue. Currently the model is much
stronger on the individual factors than on their interaction, but overall the
evidence does support the more generic conclusion that MUS in general, and
IBS and CFS specifically, are multi-factorial conditions caused and
perpetuated by several distinct processes. As such the autopoietic
explanation of MUS as proposed by the CBT model both fits the current data
and could form a theoretically coherent basis for further research. More
generally, the research bears out the over-arching CBT hypothesis that the
autopoietic interaction of distinct but linked systems could serve to produce
physical symptoms in the absence of physical pathology.


5. Treatment studies

The proof of the CBT pudding must, at least in part, be in the treating.
Treatment relies on the model to identify the elements maintaining the
autopoietic cycles, and to identify what factors made the individual
vulnerable in the first place. This is the explicit purpose of the CBT
assessment: to form a coherent multi-factorial case conceptualisation that
forms the rationale for treatment (see Deary & Chalder, 2006). In CFS
inconsistent and reduced activity, disturbed sleep and catastrophic beliefs
regarding activity and symptoms are the most commonly identified set of
factors and therapeutic targets; in IBS it is catastrophic beliefs,
behavioural avoidance and gut symptom intolerance. In as far as these factors
are altered in treatment, treatment trials serve as a test of the model,
though few have the size or finesse to isolate the "effective ingredients"
i.e. to identify which changes in which factors, or their interactions, lead
to symptomatic improvement. The purpose of the following review is to
summarise the findings of the clinical efficacy of CBT and to see if this
casts any light on the standing of the CBT model employed in treatment.

In the last five years four systematic reviews of treatment studies have been
published (Kroenke & Swindle, 2000; Allen et al., 2002; Looper & Kirmayer,
2002; Raine et al., 2002) of the MUS literature, each with a slightly
different slant. Allen et al. (2002) took the self-declaredly controversial
approach of combining all the RCTs of general psychosocial treatments for
MUS, IBS, CFS and fibromyalgia into one analysis. Their aggregate analysis
found that overall treatment effect sizes are "modest at best" with few
intention to treat analyses and very little definition of clinically
significant improvement across conditions. Theirs is the most pessimistic
analysis, and includes non-CBT therapies. The overall conclusion of the other
reviews is for a modest effect size of CBT for MUS, smaller than in anxiety
and depressive disorders, but still clinically significant. In the following
we will briefly summarise the findings reported in these reviews and also add
some notable trials subsequently reported.


5.1. General MUS

Looper and Kirmayer (2002) reported three randomised controlled trials of
individual CBT for primary care patients presenting with MUS and concluded
that CBT demonstrated a moderate effect size for reduction in somatic
symptoms. Two of these studies also reported a significant reduction in
psychological distress, one did not. In addition they reported on Hellman,
Budd, Borysenko, McClelland, and Benson (1990) randomised study of two CBT
groups compared to an attention control group. Both CBT groups produced
significant reductions in somatic symptoms and distress, this effect being
largest in the group that specifically addressed illness behaviours and
beliefs. Kroenke also reported on Lidbeck's (1997) randomised trial of a
group treatment in primary care which produced decreased symptom
pre-occupation and medication use compared to a waiting list control. There
was no observed effect on psychological distress, though in a follow up study
Lidbeck et al. (2003) reported that improvement in somatic pre- occupation
was maintained and that there was additional reduction in anxiety measures.

Since these reviews were published, other studies have been reported.
Larisch, Schweickhardt, Wirsching and Fritzche (2004) studied the effects of
a re-attribution intervention delivered by 23 trained GPs, comparing their
patient outcomes to 19 untrained GPs. They found no significant impact on
psychological symptoms (both Kroneke & Swindle, 2000; Allen et al., 2002
noted this general trend) but some improvement in physical symptoms.
Bleichhardt, Timmer, and Rief (2004) and Hiller, Fichter, and Rief (2003)
both performed RCTs in tertiary care with CBT having small but significant
effects on physical symptoms and HAD scores.

In summary there is evidence for a moderate beneficial effect of CBT for MUS
in general. However, the treatments described vary greatly in content, method
of delivery and target patient group, so conclusions about the most effective
components of treatment and precise mechanisms of change are impossible to
draw.


5.2. Chronic fatigue syndrome

Raine et al. (2002) in their review identified eight trials published since
1993. Seven of these were conducted in secondary care, one in primary care.
Five were of CBT; three are of what the reviewers called Behaviour Therapy,
also known as Graded Exercise Therapy (GET). Three of the CBT trials showed
substantial effect of CBT on CFS symptoms, two did not, one of these being
the primary care study. All three trials of GET lead to symptomatic and
functional improvement, though Wearden et al. (1998) had a smaller
improvement and a higher drop out rate. The reviewers concluded that CBT
(including GET) was effective in secondary care, but that there was little
evidence for CBT in primary care, with only one trial conducted in this
context.

Since these reviews were published there have been two further trials of GET
in CFS. Moss-Morriss et al. (2005) and Wallman, Morton, Goodman, Grove, and
Guilfoyle (2004) both showed clinically significant improvement in CFS
patients receiving GET compared to controls, as measured by symptom reports
and physical functioning. Edmonds, McGuire, and Price (2004) performed a
Cochrane Review of trials of GET for CFS and concluded that GET does lead to
significant clinical improvement, but has a higher drop-out rate than
comparable treatments. Clarke and White reach a similar conclusion in their
survey of the GET trials (Clarke & White, 2005).

Again, it is hard to disentangle the active ingredient in these treatments.
The CBT tends to involve pacing, graded increases in activity, sometimes
exercise, work on a variety of cognitions including perfectionist beliefs,
catastrophic illness beliefs and schema work. The GET trials provide a
relatively more focussed intervention, and we could easily conclude that the
reversal of de-conditioning is the effective component of this form of
treatment. Although seemingly obvious, this is not necessarily true. The
Moss-Morriss et al. (2005) GET trial demonstrated that reduced symptom focus
partly mediates improvement. We need much larger trials, and more component
analyses, before we can draw anything other than the most general conclusion
that both behavioural and cognitive interventions achieve moderate clinical
improvement in CFS. Overall these trials provide support for the prediction
of the CBT model that changing behaviours and cognitions leads to improvement
in physical symptoms, implying that the former are instrumental in their
perpetuation.


5.3. Irritable bowel syndrome

The Raine et al. (2002) review reported on twelve trials of either
Behavioural Therapy or CBT. As for CFS, there were better outcomes from those
trials conducted in secondary care, with all studies reporting improvements
in both symptoms and coping. They concluded that although there is some
evidence for the effectiveness of CBT, it is mixed, and the strongest
evidence is for anti-depressant drugs. Reviewing almost the same trials,
Allen et al. (2002) concluded that CBT has only a modest effect. More
recently Blanchard (2005) has reviewed the trials and reported a further six.
As Blanchard noted, the samples sizes have been small, the results mixed and
the treatments heterogeneous. Since this review, a large RCT in primary care
has been reported by Kennedy et al. (2005). Patients were randomised to
either six sessions of Mebeverine plus CBT or Mebeverine alone. The group who
received CBT showed greater improvement in somatic symptoms at six month
follow up, but by twelve months this between-group difference was no longer
significant. However the CBT group rated themselves as significantly less
disabled by symptoms compared to medication only controls, and this
difference persisted at twelve month follow up. This trial is notable for
both its size, for being in primary care and for its novel method of
treatment delivery, using briefly trained non-mental health professionals.

Overall the trials of CBT in IBS paint an inconclusive picture for both the
effectiveness of CBT and the validity of the CBT model, the research to date
being hampered by being mainly small trials of heterogeneous interventions.
As Blanchard (2005) notes, there is equally strong evidence for other
psychosocial interventions such as hypnotherapy.


6. Summary, conclusions and recommendations

There is fairly good evidence for the role of the elements of the CBT model
in MUS, but less evidence for the patterns of interaction of these elements.
There is general evidence that targeting maintaining factors leads to symptom
reduction, but only limited evidence for what the key factors or
interventions might be. The more vaguely conceptualised and diffuse
conditions of general MUS and CFS provide clearer empirical support for CBT
treatment than the more coherently conceptualised condition of IBS. However
this may be due to the motley nature of interventions tested in the latter,
and the preponderance of small trials. Also of note are the mixed findings
for reduction in psychological distress. Kroenke and Swindle (2000) concluded
that for all MUS, the main effect of CBT was for somatic symptoms (71%) and
that psychological distress improved in less than half the studies (46%).
This certainly questions the common assumption that improvement in somatic
symptoms is caused by improvement in distress.

Given the mixed nature of the interventions, and their relative complexity,
the most conservative conclusion from the treatment trials reviewed is that
targeting cognitive and behavioural factors can lead to physical symptom
improvement. Although this gives support to the overall spirit of the CBT
model, we are still some way from pin- pointing which interventions and which
mechanisms of change are the most important in symptom maintenance and
treatment.


6.1. The model

We suggest that we are now at the stage where research should pay more
attention to some of the components of the model and to their interaction.
Two of the predominant themes to emerge from the theoretical literature are
sensitisation and attention. These processes are not necessarily locatable,
are poorly understood, and their interaction complex. The
psychoneuroendocrinology papers reported here offer some early promise. Brain
imaging of symptom experience, informed by theoretical models, is another
potentially exciting area for further work. The links so far found between
central nervous system processes, such as the HPA axis, and immunological
processes are intriguing but far from conclusive; the causal relationships
are unclear, as are the nature of the change in these systems in different
conditions at different stages. There is however already sufficient data to
propose hypotheses about some of the important links, for example, between
life events, HPA axis and immune functioning, that could be tested in
prospective studies. More speculatively, there are indications of at least
two distinct physiological systems at work in MUS, an acute stress system and
a recuperation system. Patients or conditions more characterised by
anxiety-like responses might have different physiological markers from
conditions characterised by withdrawal and lassitude. Whether these
constitute distinct systems, and whether there is, as Dantzer (2005)
suggests, an isolatable illness response mechanism certainly deserves further
investigation. The acknowledgment that the phenomenology reported by patients
has a biological substrate will be welcomed by many patients, and is long
overdue.

Petrie and Weinman (2003) have called for more attention to be given to
symptom appraisal and we would widen this by a calling for more attention to
attention in general. The theoretical literature and some of the empirical
literature supports this mechanism as being an important part of the cycle
maintaining MUS. However there has been relatively little research on this.
Closely related to this is the work on attribution. In future work we need to
be measuring not only the nature of the attributions, but also their variety,
fixity and exclusivity. In this field a more qualitative, less theory driven
approach to attribution assessment, such as Kirmayer et al.'s (2004) might
give us more idea of the range and nature of patients versions of their
symptoms, rather than trying to corral them into the dichotomy of
psychological versus somatic.

The nature of individual differences in susceptibility to MUS would also
merit further attention. High neuroticism may offer an underlying common
mechanism for distress sensitivity and intolerance which lowers the threshold
for symptom detection (both mental and physical), and leads to increased
propensity to conditioned responses, more attention to threat stimuli and
more avoidant coping. The neuroticism concept captures many of the factors
hypothesised to be at work in MUS. This would suggest two further lines of
research. Firstly, more examination of the physiological, cognitive and
behavioural markers of N might give us more insight into the processes at
work in MUS. Secondly, longitudinal studies in N might give us a clearer idea
of what mediates and moderates development of MUS in vulnerable individuals.

The CBT model of MUS offers a previously undescribed illness mechanism
maintaining a distinct group of disorders that we might call autopoietic
conditions. The fundamental hypothesis underlying the model is that symptoms
are maintained by a self perpetuating, multi-factorial cycle. Treatment is
aimed at elaborating the unique inter-play of factors in any given patient
and dismantling the autopoietic mechanism by making changes in target areas.
In as far as treatment studies are a test of this hypothesis, it has good but
at present only indirect support. More direct research support, based on
testing this theoretical model of MUS is needed. With inter-plays of
cultural, social, cognitive, behavioural, personality and biological factors,
these conditions call for a truly multi-disciplinary research programme and a
level of inter-disciplinary understanding which is rarely witnessed and
technically hard to achieve. Diseases which are confined to one organ system
are relatively easy to isolate and study, as reflected in medical and
research establishments of increasing specialism. Our understanding of MUS
has been hampered by this as each specialism either denies the reality of
these conditions or attempts to limit their understanding to its own field.
As Rief and Sharpe (2004) suggest, our understanding of MUS calls for a
reversal of this trend. We need not only multi-modal treatments, but a
research programme that is informed by the knowledge that physical symptoms
can be maintained systemically, through the interaction of diverse processes
and not just through pathophysiology. This work has barely begun.


6.2. Treatment

Distress intolerance is as a key theme in the CBT model of MUS maintenance.
Symptoms are perceived as aversive/ threatening, which triggers a
physiological response, which serves to maintain avoidance, symptom focus and
symptoms. One hypothesis would be that developing the ability to tolerate
symptoms whilst not letting them dictate behaviour would be a promising line
of enquiry. The so called third wave of CBT, particularly Acceptance and
Commitment Therapy (see Hayes, Strosahl, & Wilson, 1999), with its emphasis
on distress tolerance and goal maintenance would seem well suited as a
paradigm to apply to these conditions, as would the related intervention of
mindfulness.

Another approach to treatment that enjoys strong theoretical support but
little empirical evidence, lies in the nature of the CBT rationale for
treatment. Powell, Nye, and Edwards (2001) "frontloaded" their CFS treatment
with a very detailed physiological explanation for symptoms and then used a
relatively short GET intervention, which proved comparably effective to
longer ones. Several of the papers quoted here show that particular types of
illness attributions, particularly very fixed or catastrophic ones, are
associated with poor outcome. Kirmayer et al. (2004) reported some
explanation is better than none, and that the very process of helping a
person construct a narrative in a research interview was beneficial. This
component of CBT, constructing a model of the patient's symptoms based on
some of the processes described above, could be tested as an intervention in
itself. Certainly, spending time constructing a credible treatment rationale
is time well spent.

Most GPs want to manage MUS in primary care (Reid, Whooley, Crayford, &
Hotopf, 2001), although few feel that there is any effective treatment
available. As most of the reviewers have noted, the preponderance of trials
of treatment for MUS have been done in secondary care by specialists, mostly
in mental health. Very few studies have tested either primary care delivery
or training GPs and other non-mental health professionals to deal with MUS.
There have been exceptions. Fink, Rosendal, and Toft (2002) have described a
GP training course to increase awareness of MUS and its application in a
trial (Rosendal, Bro, Fink, Christensen, & Olesen, 2003). Smith et al. (2003)
trained practice nurses to treat MUS; Kennedy et al. (2005) used nurses
trained in CBT to implement an intervention for IBS in primary care.

There is currently work amongst our team using a similar approach in
diabetes, in functional dysphonia and in depression in cancer. Training non
mental health professionals to deliver cognitive behavioural treatments for
symptoms (both explained and unexplained) would seem to be a promising and
cost-effective way forward to target the unmet need in MUS.

With some exceptions, (McCrone, Risdale, Darbishire, & Seed, 2004), we lack
good data on cost effectiveness. As trials get larger and move towards
primary care, health economics will be vital in assessing the value of these
treatments and in assessing the costs versus the benefits of disseminating
CBT skills to non-mental health professionals. Certainly, if effective, this
would be one way of implementing the "cadre of well trained therapists who
are knowledgeable in the principles and practice of CBT" that Mai (2004)
recommends be available in primary care.

What about prevention? This work may be far off, but there are some
indications of how we could proceed. Prevention is of course predicated on
being able to predict increased likelihood of occurrence and we can, to an
extent, do this. Individuals who are high N, who have experienced childhood
adversity or parental illness, who experience a serious virus and/or
prolonged life events and stressors, are going to be, the theory and data
would suggest, more likely to develop MUS. Longitudinal work, of the kind
being conducted in Heidelberg (see Amelang, 1997) studying personality
predictors of physical illness would be necessary to see if personality is a
genuine marker of vulnerability, and if so to what degree. Hotopf (2004) has
drawn our attention to the vital role that both doctors and parents can play
in the development, or prevention, of MUS in these vulnerable patients. The
right advice derived from a collaboratively constructed model of symptom
experience, could be crucial in preventing or ameliorating MUS. In the CBT
model, we may just have the means to do this.


Figure caption

Fig. 1.
Expanded CBT model of hypothesised autopoietic cycle of symptom maintenance.


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