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Date:    Tue, 3 Apr 2007 11:47:35 -0400
From:    Fred Springfield <fredspringfield VERIZON.NET>
Subject: RES: Protocol for the PACE trial: a randomised controlled  trial of adaptive pacing, cognitive behaviour therapy, and graded  exercise, as supplements to standardised specialist medical care  versus standardised specialist medical care alone for patients with  the chronic fatigue syndrome/myalgic encephalomyelitis or  encephalopathy

Protocol for the PACE trial: a randomised controlled trial of adaptive
pacing, cognitive behaviour therapy, and graded exercise, as supplements to
standardised specialist medical care versus standardised specialist medical
care alone for patients with the chronic fatigue syndrome/myalgic
encephalomyelitis or encephalopathy.

Journal: BMC Neurol. 2007 Mar 8;7:6.

White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group.

Affiliation: Department of Psychological Medicine, Queen Mary School of
Medicine and Dentistry, St Bartholomew's Hospital, London, UK.
p.d.white@qmul.ac.uk <p.d.white@qmul.ac.uk>

NLM Citation: PMID: 17397525


BACKGROUND: Chronic fatigue syndrome (CFS, also called myalgic
encephalomyelitis /encephalopathy or ME) is a debilitating condition with
no known cause or cure. Improvement may occur with medical care and
additional therapies of pacing, cognitive behavioural therapy and graded
exercise therapy. The latter two therapies have been found to be
efficacious in small trials, but patient organisations surveys have
reported adverse effects. Although pacing has been advocated by patient
organisations, it lacks empirical support. Specialist medical care is
commonly provided but its efficacy when given alone is not established.
This trial compares the efficacy of the additional therapies when added to
specialist medical care against specialist medical care alone.

METHODS: 600 patients, who meet operationalised diagnostic criteria for
CFS, will be recruited from secondary care into a randomised trial of four
treatments, stratified by current co morbid depressive episode and
different CFS/ME criteria. The four treatments are standardised specialist
medical care either given alone, or with adaptive pacing therapy or
cognitive behaviour therapy or graded exercise therapy. Supplementary
therapies will involve fourteen sessions over 23 weeks and a booster
session at 36 weeks. Outcome will be assessed at 12, 24, and 52 weeks after
randomisation. Two primary outcomes of self-rated fatigue and physical
function will assess differential effects of each treatment on these
measures. Secondary outcomes include adverse events and reactions,
subjective measures of symptoms, mood, sleep and function and objective
measures of physical activity, fitness, cost-effectiveness and
cost-utility. The primary analysis will be based on intention to treat and
will use logistic regression models to compare treatments. Secondary
outcomes will be analysed by repeated measures analysis of variance with a
linear mixed model. All analyses will allow for stratification factors.
Mediators and moderators will be explored using multiple linear and
logistic regression techniques with interactive terms, with the sample
split into two to allow validation of the initial models. Economic analyses
will incorporate sensitivity measures.

DISCUSSION: The results of the trial will provide information about the
benefits and adverse effects of these treatments, their cost-effectiveness
and cost-utility, the process of clinical improvement and the predictors of
efficacy.


[This is an Open Access article.  The full text is available free at
http://www.biomedcentral.com/1471-2377/7/6

The PDF version is available for free at
http://www.biomedcentral.com/content/pdf/1471-2377-7-6.pdf ]

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------------------------------

Date:    Tue, 3 Apr 2007 17:52:58 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: Protocol PACE trial

Source: BMC Neurology
        Preprint/Vol 7, 6
Date:   March 8, 2007
URL:    http://www.biomedcentral.com/1471-2377/7/6
        http://www.biomedcentral.com/1471-2377/7/6/prepub


[Study protocol]

Protocol for the PACE trial: A randomised controlled trial of adaptive
pacing, cognitive behaviour therapy, and graded exercise as supplements to
standardised specialist medical care versus standardised specialist
medical care alone for patients with the chronic fatigue syndrome/myalgic
encephalomyelitis or encephalopathy
--------------------------------------------------------------------------
Peter D White(1), Michael C Sharpe(2), Trudie Chalder(3), Julia C DeCesare
(4) and Rebecca Walwyn(5) for the PACE trial group(4)
1 Department of Psychological Medicine, Queen Mary School of Medicine and
  Dentistry, St Bartholomew's Hospital, London, UK
2 Psychological Medicine and Symptoms Research Group, University of
  Edinburgh, Royal Edinburgh Hospital, Edinburgh, Scotland, UK
3 Academic Department of Psychological Medicine, Guy's, King's and St
  Thomas' School of Medicine, Weston Education Centre, London, UK
4 PACE Trial Coordinating Centre, Queen Mary School of Medicine and
  Dentistry, St Bartholomew's Hospital, London, UK
5 Mental Health & Neuroscience Clinical Trials Unit (MH&N CTU), Institute
  of Psychiatry, London, UK

Received  30 October 2006
Accepted  8 March 2007
Published 8 March 2007


Abstract

Background
Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis/
encephalopathy or ME) is a debilitating condition with no known cause or
cure. Improvement may occur with medical care and additional therapies of
pacing, cognitive behavioural therapy and graded exercise therapy. The latter
two therapies have been found to be efficacious in small trials, but patient
organisations' surveys have reported adverse effects. Although pacing has
been advocated by patient organisations, it lacks empirical support.
Specialist medical care is commonly provided but its efficacy when given
alone is not established. This trial compares the efficacy of the additional
therapies when added to specialist medical care against specialist medical
care alone.

Methods/Design
600 patients, who meet operationalised diagnostic criteria for CFS, will be
recruited from secondary care into a randomised trial of four treatments,
stratified by current comorbid depressive episode and different CFS/ME
criteria. The four treatments are standardised specialist medical care either
given alone, or with adaptive pacing therapy or cognitive behaviour therapy
or graded exercise therapy. Supplementary therapies will involve fourteen
sessions over 23 weeks and a 'booster session' at 36 weeks. Outcome will be
assessed at 12, 24, and 52 weeks after randomisation. Two primary outcomes of
self-rated fatigue and physical function will assess differential effects of
each treatment on these measures. Secondary outcomes include adverse events
and reactions, subjective measures of symptoms, mood, sleep and function and
objective measures of physical activity, fitness, cost-effectiveness and
cost-utility. The primary analysis will be based on intention to treat and
will use logistic regression models to compare treatments. Secondary outcomes
will be analysed by repeated measures analysis of variance with a linear
mixed model. All analyses will allow for stratification factors. Mediators
and moderators will be explored using multiple linear and logistic regression
techniques with interactive terms, with the sample split into two to allow
validation of the initial models. Economic analyses will incorporate
sensitivity measures.

Discussion
The results of the trial will provide information about the benefits and
adverse effects of these treatments, their cost-effectiveness and
cost-utility, the process of clinical improvement and the predictors of
efficacy.


Introduction

The chronic fatigue syndrome (CFS) is a condition characterised by chronic
disabling fatigue and other symptoms, which are not better explained by an
alternative diagnosis [1-3]. Myalgic encephalomyelitis/encephalopathy (ME)
refers to a severe debilitating illness thought by some to be a separate
illness, but by others to be synonymous with CFS [2-6]. In keeping with the
MRC Research Advisory Group report and the CMO's working group report, we
will refer to the illness using both terms: CFS/ME [4,6]. The prevalence of
CFS/ME in the population is between 0.4 and 2.5% [3,4,6]. A working group,
reporting to the Chief Medical Officer (CMO) for England, concluded; "CFS/ME
is a relatively common clinical condition, which can cause profound, often
prolonged, illness and disability, and can have a substantial impact on the
individual and the family" [4]. As many as half the patients with CFS/ME are
unemployed [7], and they have 10 times the amount of sick-leave of other
general medical outpatients [8]. The prognosis is poor: in primary care only
a third improve by one year, and of those referred to secondary care less
than 10% return to pre-morbid functioning [3,9]. The management of patients
with CFS/ME currently consumes significant resources in both primary and
secondary care with uncertain benefit to patients [4,5]. CFS/ME patients use
an annual average of 13 visits to their general practitioner and 5 visits to
secondary care [7]. There is now some evidence that specific treatments can
improve these poor outcomes. The CMO's working group concluded; "Therapeutic
strategies that can enable improvement include graded exercise/activity
programmes, cognitive behaviour therapy, and pacing" [4]. However this
positive statement was balanced in the report by other statements: first the
concern of patient organisations that graded exercise therapy (GET) may
sometimes worsen symptoms and disability, and second that pacing, although
widely advocated by patients' organisations, is as yet unsupported by
scientific evidence.


Efficacy - Relevant studies/trials

Two independent systematic reviews have found that rehabilitative cognitive
behaviour therapy (CBT) and GET were the most promising treatments for CFS/ME
in secondary care [5,10-12]. The published trials of these treatments were
however also criticized for being too small, too selective, and for using
different outcome measures. No other treatments for CFS/ME have so far been
shown to be helpful in more than one RCT [5,12]. CBT is a more complex
therapy than GET, requiring highly trained therapists, and is therefore less
readily available. In contrast, surveys carried out by Action for M.E. of
their members have indicated that CBT and GET can sometimes make people worse
[13-15]. Pacing and rest were reported to be more helpful [13]. Pacing has
been described in the scientific literature as a lifestyle management that
allows optimal adaptation to the illness, including an appropriate balance of
rest and activity [4,16]. It has been advocated by exponents of the "envelope
theory" of CFS/ME, which states that a patient has a fixed and finite amount,
or "envelope", of energy that they must adapt to by managing their activity
[16]. A non-randomised comparison of adaptive (rather than rehabilitative)
CBT, which included adaptive pacing therapy (APT) based on this model, found
that, although fatigue improved, this treatment was no more effective than
the control treatment in reducing disability [17]. A recent systematic review
concluded that there was insufficient evidence to recommend APT at present
[5,10,12]. In a similar way there is little RCT evidence of the efficacy of
specialist medical care. There is therefore an urgent need to: (a) compare
the supplementary therapies of both CBT and GET with both APT and
standardised specialist medical care (SSMC) alone, seeking evidence of both
benefit and harm (b) compare supplementary APT against SSMC alone and (c)
compare the supplementary therapies of APT, CBT and GET in order to clarify
differential predictors and mechanisms of change.


Differential outcomes

Because CBT and GET are both based on a graded exposure to activity, they may
preferentially reduce disability, whilst APT, being based on the theory that
one must stay within the limits of a finite amount of "energy", may reduce
symptoms, but at the expense of not reducing disability. By measuring both
symptoms and disability as our primary outcomes, we will be able to test a
secondary hypothesis that these treatments may differentially affect symptoms
and disability.


Process of treatment

We do not know the mechanisms of successful treatment for CFS/ME. Do illness
beliefs or focusing of attention on symptoms (symptom focusing) need to be
changed for CBT to be effective? Or do CBT and GET both work by improving
tolerance to activity? Is increased physical fitness essential to recovery or
not? How important is the alliance between therapist and patient? Is it
necessary to adapt to the limitations imposed by the illness to reduce
fatigue? A greater understanding of these processes will shed light on the
essence of improvement and allow the development of more efficient
treatments.


Predictors of outcome

Predictors of a negative response to treatment found in previous studies
include having a mood disorder, membership of a self-help group, being in
receipt of a disability pension, focusing on physical symptoms, and pervasive
inactivity [3,18,19]. There is however no general agreement on which are the
most important predictive factors.


Cost-effectiveness and cost utility

A recent study has suggested that there is little difference in the
cost-effectiveness of CBT and GET for chronic fatigue in primary care, and
both were more expensive and more effective than standard care [20].
However, only one-third of patients in this study had CFS/ME and it was not
powered to detect differences for this subgroup. There are currently only
limited published data on the cost-effectiveness of treatments specifically
for CFS/ME.


Risks and benefits

There is a discrepancy between surveys of CFS/ME patient group members and
published evidence from trials. Some CFS/ME charity members have reported
that they feel worse after exercise therapy, and to a lesser extent CBT
[13,14], whereas the trial evidence suggests minimal or no risk with these
treatments. A further survey by Action for M.E. of their members suggests
that reports of deterioration with therapy are related to either poorly
administered treatment or lack of appropriate professional supervision [15].
The individual treatment programmes used in PACE will minimise this risk by
being mutually agreed between participant and therapist, carefully monitored
and flexibly implemented. We will also carefully monitor all participants for
any adverse effects of the treatments, and will undertake a detailed
assessment, at home if necessary, of any participant who reports
deterioration or who withdraws from treatment, following which they will be
offered appropriate help.


Rationale

The results of this trial will: (a) allow people with CFS/ME, clinicians and
health planners to choose treatment on the basis of both efficacy and cost;
(b) provide evidence about the efficacy and adverse effects of the four
treatments (APT, CBT, GET and SSMC); (c) provide the first test of SSMC plus
pacing against SSMC alone; (d) indicate which patient characteristics predict
a successful outcome; (e) identify which patient characteristics predict
response to which treatment and (f) define the essential aspects of effective
treatment as a first step toward the development of more efficient therapies.

The trial will recruit new patients from secondary care clinics run by three
different disciplines (immunology, infectious disease and psychiatry) in six
different centres in both England and Scotland. This recruitment plan will
ensure sufficient heterogeneity to allow generalisation of the findings. We
will not recruit directly from primary care because we wish to compare the
efficacy of these treatments in patients whom GPs regard as requiring
additional help and who are likely to have a worse prognosis (one of the
recommendations CMO's report [4]). Furthermore, direct recruitment from
primary care has been found to be problematic in previous studies. Two recent
trials of treatment for prolonged fatigue (not CFS/ME) using large and well
established primary care research networks recruited only 46 patients with
CFS/ME in three years [21] and 44 patients in 2.5 years [22].


Methods/Design

Aims

The main aim of this trial is to provide high quality evidence to inform
choices made by patients, patient organisations, health services and health
professionals about the relative benefits, cost-effectiveness, and
cost-utility, as well as adverse effects, of the most widely advocated
treatments for CFS/ME.

The secondary aims of this trial are to investigate the mechanisms and
predictors of a successful outcome.


Objectives

The PACE trial is designed to answer the following questions:

Primary objectives
(1) Is APT and SSMC more effective than SSMC alone in reducing (i) fatigue,
    (ii) disability, or (iii) both?
(2) Is CBT and SSMC more effective than APT and SSMC in reducing (i)
    fatigue, (ii) disability or (iii) both?
(3) Is GET and SSMC more effective than APT and SSMC in reducing (i)
    fatigue, (ii) disability, or (iii) both?
(4) Are the active rehabilitation therapies (of either CBT or GET) more
    effective than the adaptive approach of APT when each is added to SSMC,
    in reducing (i) fatigue and/or (ii) disability?
(5) What are the relative cost-effectiveness and cost-utility of these
    treatments?

NB For the sake of brevity, the rest of the protocol will refer to the
four treatment arms as APT, CBT, GET and SSMC rather than APT plus SSMC,
CBT plus SSMC, GET plus SSMC and SSMC alone.

Secondary objectives
The secondary analyses are exploratory but we will be guided by previously
published findings.
(1) Do different treatments have differential effects on outcomes (i.e.
    fatigue versus physical disability)?
(2) What baseline factors (other than randomised treatment) predict a
    reduction in (i) fatigue, (ii) disability in all participants?
(3) Are there differential predictors of response to APT, CBT, GET, and SSMC
    (i.e. treatment-covariate interactions)?
(4) Are there changes in factors (time-dependent covariates) during the
    earlier stages of treatment that (after controlling for baseline overall
    and differential predictors) are associated with outcome 1 year after
    randomisation?
(5) Are the differences across treatment groups in the primary outcomes
    associated with similar differences in secondary outcomes (e.g. in global
    change, mood, quality of life and objective measures of physical activity)?

Hypotheses of efficacy
(1) APT is more effective than SSMC alone in reducing (i) fatigue, (ii)
    reducing physical disability and in reducing (iii) both.
(2) CBT is more effective than APT in reducing (i) fatigue, (ii) disability
    and in reducing (iii) both
(3) GET is more effective than APT in reducing (i) fatigue, (ii) disability
    and in reducing (iii) both
(4) The active rehabilitation therapies (of either CBT or GET) are more
    effective than the adaptive approach of APT in reducing fatigue, physical
    disability and both
(5) CBT is more effective than SSMC in reducing (i) fatigue, (ii) disability
    and in reducing (iii) both
(6) GET is more effective than SSMC in reducing (i) fatigue, (ii) disability
    and in reducing (iii) both
Other secondary hypotheses will be stated pre-hoc in an Analysis Strategy
document.


Type of design

A four arm, randomised multi-centre parallel group controlled trial of
patients who meet operationalised criteria for CFS/ME, with follow-up for 52
weeks (see Figure 1).


Trial treatments - interventions and control

There are four treatment arms. SSMC is given to all participants. Three
quarters will also receive one of the following supplementary therapies:
APT, CBT or GET.


Duration

Patients will be assessed for eligibility and those who are eligible and give
consent will be randomly allocated to one of four treatments. Treatment will
start as soon as possible after randomisation. The final outcome assessment
will be at 52 weeks post randomisation.


Number and source of participants

We will study 600 participants, recruited from new patient attenders, over
approximately three years in six centres. All participants will be attending
secondary care chronic fatigue clinics.

All centres have reported that they currently see a minimum of 100 new
patients per year. We estimate that 60 will meet eligibility criteria, and we
estimate that two thirds of these will agree to enter the trial, giving
potentially a minimum of 40 participants per centre. In previous trials of
both CBT and GET, only 7 and 15% of eligible participants refused to
participate in GET trials [23,24] and 3, 10 and 26% of those eligible refused
to participate in the three previous CBT trials [18,25,26]. We are therefore
confident that recruitment is feasible and that the trial will recruit 600
participants over three years.


Projected recruitment

Recruitment estimates are based upon 80% efficiency for the first three
months rising to 100% efficiency by six months.

Inclusion criteria
1. Both participant and clinician agree that randomisation is acceptable.
2. The participant has given written informed consent.
3. The participant meets operationalised Oxford research diagnostic criteria
   for CFS [2].
4. The participant's Chalder Fatigue Questionnaire score is 6 or more
   [27].
5. The participant's SF-36 physical function sub-scale score [28] is 65 or
   less.
6. The participant is aged at least 18 years old.

Exclusion criteria
1. All potential participants will be screened for medical exclusions, by
   history and physical examination [1,2,4,29]. Appropriate investigations
   [4,29] will be undertaken by either the referring doctor or the centre
   doctors (checked by the research nurse) in the six months before baseline
   screening. Patients with a relevant alternative medical diagnosis will be
   excluded [2]. Investigations will be those recommended by the Royal
   Colleges' Report on CFS/ME and the CMO's working group report [4,29].
2. The research nurse (RN) will use a standardised psychiatric interview
   (the Structured Clinical Interview for DSM-IV - SCID) [30], under
   supervision by a participating centre PI or nominated deputy, to exclude
   those who are at significant risk of self-harm and those with psychiatric
   exclusions listed in the Oxford diagnostic criteria for CFS [2].
3. Patients who are considered by the RN, in discussion with their centre
   leader, to be unable to do one or more of the trial therapies or to
   complete all trial measures or for whom participation in the PACE trial
   would be inappropriate to their clinical needs (e.g. someone with
   significant post-traumatic stress disorder or borderline personality
   disorder).
4. Patients who have previously attended a PACE centre specialist fatigue
   clinic and received a course of treatment, from a specialist, considered
   to be similar to SSMC or any of the supplementary therapies of APT, CBT,
   or GET as delivered in the trial will be excluded from taking part in the
   trial.


Screening/Baseline Procedures

Written informed consent will be taken before any trial related procedure
takes place. Therefore PACE will utilise a two-stage consent/enrolment
process. In the first stage the patient will consent to take part in the
eligibility and baseline assessments and in the second stage the patient will
consent to the full trial including randomisation, treatment and follow-up
assessments. This has the added advantage of allowing one week's
consideration by potential participants before consenting to the full trial.


Data recording and Case Report Forms

Data will be recorded on Case Report Forms (CRFs). These will be completed by
the patient for the self-report measures, and all other data will be
collected and completed by the RN. The CRFs will be checked for completeness
and legibility by the RN before being entered onto the trial database by a
local data manager (DM). Once data has been entered onto the local database,
the data will be transferred to the senior data manager on the trial who will
compare the hard copy CRFs with the database to check accuracy. S/he will
check all the primary outcome variables and a randomly chosen 20 percent of
the other variables. All CRFs for the first ten patients randomised per
centre will be double checked. If there are any errors on primary outcomes,
or greater than 1% errors of other variables, 100% data checks will be
completed until the error rate ceases or drops. The database will not
include the assigned treatments – these will be recorded in a separate
database, in order for the statistician analysing the data to remain blind to
treatment allocation.


Initial screening for eligibility - visit 0 (clinic doctor)

New referrals to the outpatient clinics may be received from GPs or any other
appropriate medical practitioner. Each clinic doctor will ensure that all
consecutive new outpatients with a clinical diagnosis of CFS/ME are
considered for the trial (i.e. if thought to be eligible they are told about
the trial). Each centre leader will keep a trial log-book of every new
chronic fatigue outpatient referral. This log book will detail each patient
seen, whether or not they were referred for the trial and the reasons if not.

Where the patient is thought to be suitable by the clinic doctor (with a CFQ
score of 6 or above and an SF-36 score of 65 or below), and the patient
agrees to be assessed for eligibility, the clinic doctor will forward the
patient's contact details to the RN. The clinic doctor will give the patient
the trial Participant Information Sheet. The RN will contact the patient to
arrange the first research visit (visit 1).


Telephone assessment

The RN will contact patients within 24 hours of receipt of referral, who have
been referred by the clinic doctor for the PACE trial, by telephone. The RN
will check that the patient has received a Participant Information Sheet from
the clinic doctor, and if they express interest in the trial, will arrange a
date for the patient to attend the first research assessment interview (visit
1) as soon as possible (within one week of referral, but not more quickly
than 48 hours after receipt of the Participant Information Sheet).


Eligibility assessment and consent for assessment - visit 1

All of the following eligibility criteria must be fulfilled for the
patient to participate:
1. The patient has a clinical diagnosis of CFS [2].
2. The patient does not have treatment needs that would make participation
   in the PACE trial inappropriate.
3. The patient is aged 18 years or above.
4. The patient can speak and read English at a level adequate for
   participation in the trial, as assessed by the RN. The reasons for this
   include the need to self-rate written primary and secondary outcomes using
   scales that have not been validated in non-English languages; the need to
   receive therapy that can be checked for quality and manual adherence; and
   the prohibitive cost of providing therapy in more than one language.
5. The Chalder Fatigue Questionnaire score is 6 or more [27].
6. The SF-36 physical function sub-scale score is 65 or less [28].
7. The Structured Clinical Interview for DSM-IV (SCID i/P; non-patient
   edition with psychotic screen) [30], will be used to exclude patients with
   psychiatric exclusions [2]. If a participant or patient is found to have a
   current psychiatric diagnosis on the SCID, the RN will inform the clinic
   doctor. All SCIDs will be audio-recorded for the purposes of quality
   control and RN supervision; the supervision being provided by the centre
   leader or their nominated deputy.
8. Patients who are considered by the RN in discussion with their centre
   leader to be unable to do one or more of the trial therapies or to
   complete all trial measures (travel expenses will be offered for therapy
   and research assessments).
9. There is no contra-indication to any of the treatments that might be
   provided in the trial.
10. Permission has been obtained to review medical notes.

In addition, the following assessments will be completed at baseline visit 1:
1. Participant demographic details will be collected (including date of
   birth, age, sex, ethnicity, marital or partner status, years of education,
   occupation)
2. Duration of CFS/ME (months)
3. Medical History
4. Co-morbid and current medical conditions
5. Current and specific membership of a self-help group (specific question)
6. Body Mass Index (BMI) (measure weight in kg and height in metres)
7. The six-minute walking test [31]

At the end of this visit the RN will give the participant the further
baseline self-report questionnaires to complete at home and return at visit
2. These questionnaires are as follows:
1. The Chronic Disease Self-Efficacy measure [32]
2. The Work and Social Adjustment Scale [33]
3. Symptom Interpretation Questionnaire [34]
4. Physical Symptoms (Patient Health Questionnaire; PHQ-15) [35]
5. Exercise and Activity scale [36]
6. Jenkins Sleep Scale of subjective sleep problems [37]
7. The Hospital Anxiety and Depression Scale (HADS) [38]
8. The EuroQOL (EQ-5D) [39]
9. The RN will also fit the actometer [18] to the patient with an appropriate
   explanation and ask them to wear it until return on visit 2 or for one week
   (whichever is soonest). After visit 1 the research nurse will discuss the
   patient's potential eligibility with the centre leader.


Eligibility assessment and consent for trial - visit 2

At visit 2 to the RN (after one week) the patient will return the actigraphy
watch. If the patient meets all of the eligibility criteria and none of the
exclusion criteria, understands the purpose of the trial and is willing to
give informed consent to be randomised, treated and followed up, they will
then sign the second consent form to participate in the full trial.


Completion of baseline assessment

The following baseline assessments will be completed at visit 2:
1. Current medications and therapies (including complementary and alternative
   treatments)
2. The CDC criteria for CFS [1]
3. The London criteria for myalgic encephalomyelitis [40]
4. Presence or absence of fibromyalgia (using chronic widespread pain
   criteria only and not tender points) [41]
5. Preferred treatment group (single question)
6. The Client Service Receipt Inventory (CSRI), adapted for use in CFS/ME [42]
7. The self-paced step test of fitness [43]
8. The Borg Scale of perceived physical exertion, scored once immediately
   after the step test [44]
9. The actigraphy watch will be removed and the actigraphy data [18] (as
   initiated at visit 1 with the research nurse) will be downloaded.


Randomisation and Enrolment procedure

Participants will be allocated to one of the four trial arms (ratio 1:1:1:1)
by the Mental Health & Neuroscience Clinical Trials Unit (MH&N CTU) based at
the Institute of Psychiatry. Allocation will be stratified by centre, CDC
Criteria (met or unmet), London Criteria (met or unmet) and depressive
disorder (major, minor depressive episode and dysthymia being present or
absent) using minimisation with a random component [45]. The stratification
on these criteria is to ensure equal proportions in each treatment arm. The
first N cases (N will not be disclosed) will be allocated using simple
randomisation to further enhance allocation concealment.

Once an eligible participant has completed the baseline assessment and given
written informed consent, the RN will contact the MH&N CTU for treatment
allocation by facsimile, giving the criteria needed for randomisation.
Minimisation is carried out with a random component using a customised
Microsoft Access database which will be used to hold the basic details
collected to facilitate subsequent verification and to generate the
allocation. Allocation is concealed because an independent group are
responsible for this allocation. The confirmation of stratification details
and treatment allocation will be communicated by email or facsimile to the RN
within 24 hours. The RN sends back an acknowledgement of receipt to the CTU.
This whole procedure is kept independent and separate from the trial
statisticians. The RN will on the same day inform the participant of his/her
treatment group in person or by phone, and will also inform the SSMC doctor
and appropriate therapist. The therapist will contact the participant to
arrange the first treatment appointment as soon as possible (within 5 working
days). The SSMC doctor will also arrange to see the participant within one
month of treatment allocation. The individual assignments will be available
to the local team on a need-to-know basis, with the exception of the trial
statisticians.


Participant Identification Number

The participant identification number (PIN) will be a five digit number
whereby the first two digits denote the centre and the remaining three denote
the participant number by centre allocated in order of the patient entering
the screening phase. Therefore every patient who consents to baseline and
eligibility assessment will have a PIN, but not all will be randomised due to
some being ineligible or not giving further consent.


Randomised treatments

Apart from those receiving SSMC alone, all participants will be offered equal
therapist time; 90 minutes in the first session, and 14 subsequent sessions
of 50 minutes. The 15th session will be a "booster" session given at week 36,
thirteen weeks after the 14th session, itself given at 23 weeks, which will
be the last week for therapy. Therapy sessions 2 to 15 need not last the full
50 minutes if not required. If both therapist and participant believe that
the next planned session is redundant because therapy is going so well, the
next session may be omitted, with a note made as to the reasons why.

If the participant is unable to attend an appointment in person (e.g. due to
feeling too disabled or due to intercurrent ill-health), and this cannot be
re-arranged within five working days, and if agreed by both the therapist and
participant, this session may be held over the telephone either at the
pre-arranged time or within five working days of the original appointment. If
the session does not take place within this time, the visit will be recorded
as a DNA (Did Not Attend). Ideally, no more than four sessions of the first
14 sessions should be held in this way, and they should not be sequential.
However, we believe it would be better that the participant receives some
therapy rather than none at all and this will be judged on a per-participant
basis. For this reason, if the choice is between not holding a session and a
telephone session, a telephone session will always be offered even if there
already have been four telephone sessions. This policy is supported by the
results of one RCT and an open trial having suggested that two of the
therapies (CBT and GET) delivered by telephone sessions following a face to
face initial assessment is efficacious [46,47]. The fifteenth session will be
held face-to-face, if at all possible, but even this may be held by telephone
if the alternative is non-attendance.

We have chosen 15 sessions for all supplementary treatments on the basis of
the previous trials of CBT and GET [18,23-26], as well as extensive clinical
experience. RCTs of the least effective CBT and GET trials used 6 and 8
sessions [25,48]. Although one study of a pragmatic rehabilitation found that
only 4 sessions were helpful [47], we suspect that this result may have been
related to the lack of a 'treatment as usual' control group, and that more
than four sessions are necessary to achieve change. A two year follow-up of
this trial showed that the maximal face-to-face intervention had better
efficacy by this time [19]. All interventions will be based on manuals,
revised following feedback from both patients and therapists after piloting
the manuals and therapies on patients outside of the trial.


Adaptive Pacing Therapy

APT will be based on the illness model of CFS/ME as a currently undetermined
organic disease, with the assumption that APT can improve quality of life,
although not affect the core disease, other than providing the best
conditions for natural recovery. APT is essentially an energy management
approach, which involves assessment of the link between activity and
subsequent symptoms and disability, establishing a stable baseline of
activity using a daily diary, with advice to plan and pace activity in order
to avoid exacerbations. Strategies include developing awareness of early
warning of exacerbations; limiting demands; regular planned rest and
relaxation, and alternating of different sorts of activities. The aim is to
achieve optimal adaptation to the illness [4,16,17]. The patient charity
Action for M.E. have helped in the design of the APT manual and have endorsed
this version of pacing, which is based on what is published and what patients
and clinicians have reported as helpful. Both therapists and participants
will receive separate manuals.


Cognitive Behaviour Therapy

CBT will be based on the illness model of fear avoidance, used in the three
positive trials of CBT [18,25,26]. There are three essential elements: (a)
Assessment of illness beliefs and coping strategies, (b)  structuring of
daily rest, sleep and activity, to establish a stable baseline of general
activities, with a graduated return to normal activity, (c) collaborative
challenging of unhelpful beliefs about symptoms and activity. Both therapists
and participants will receive separate manuals.


Graded Exercise Therapy

GET will be based on the illness model of deconditioning and exercise
intolerance, used in the previous trials [23,24,47]. Therapy involves an
assessment of physical capacity, establishing a stable baseline level of
physical activity, negotiation of an individually designed home exercise
programme with set target heart rates and times, and participant feedback
with mutual planning of the next fortnight's exercise programme. Both
therapists and participants will receive separate manuals.


Standardised Specialist Medical Care

SSMC will be given to all participants. This will include visits to the
clinic doctor with general, but not specific advice, regarding activity and
rest management, such as advice to avoid the extremes of exercise and rest,
as well as pharmacotherapy for specific symptoms and comorbid conditions.
SSMC is standardised in the SSMC Doctor's Manual. As well as this, SSMC
participants, like all other participants, will already have received the
Patient Clinic Leaflet (PCL). The PCL is a generic leaflet explaining what
CFS/ME is, its likely causes, and available treatments. There will be no
additional therapist involvement. In particular there will be no diary
monitoring with consequent advice. The number of SSMC outpatient sessions
will be recorded, along with any treatments given for each participant by the
SSMC doctor. Participants will be seen by their SSMC doctor a minimum of
three times after randomisation, with the first SSMC appointment taking place
as soon as possible after randomisation, and within one month. Further
sessions will be determined by clinical need. Trial therapists, participants
and general practitioners can request an unplanned clinical review by the
SSMC doctor.


Departures from randomised treatment

We will use the following strategies to minimise missing data in primary
outcomes. Participants who drop out of treatment will be assessed as soon as
possible, rather than waiting for the normal follow-up. Those who cannot
attend clinic will be offered home assessments by the RN (or failing this
assessment by telephone or by post), or centre leader as appropriate. If that
is not achieved, we will seek to obtain outcome data by use of either postal
or e-mail questionnaires, supplemented by telephone calls if necessary.


DNAs from treatment

The therapist (if they have one) or SSMC doctor will contact the participant
by telephone in the first instance to ascertain the problem of attendance,
and will discuss the appropriate solution with the participant. Choices
include a telephone session or a re-arranged face-to-face session, so long as
the latter is within five working days. Alternatively the session stays a
DNA and is recorded as such. If the participant considers that they are
deteriorating the policy for this problem will be enacted.


Clinician/Researcher withdrawal of participant from treatment

The reason for this will be recorded. When this occurs, the centre leader or
nominee should assess the participant clinically within a week, and arrange
appropriate care. Every effort will be made to obtain the two primary
outcomes and the CGI (to assess illness progression), which should be scored
in order to provide some outcome data. Such participants' data will be
included in the trial analysis. If the participant will still consent to
research (RN) follow-up, this will continue as normal.


Participant withdrawal of consent to randomised treatment

In the first instance, the therapist (if they have one) or SSMC doctor will
contact the participant by telephone to ascertain the reason for drop-out, if
the participant is willing to share this, and will discuss the appropriate
solution with the participant and then the centre leader. If the participant
considers that they are deteriorating, but does not wish to talk to the
therapist or SSMC doctor, the centre leader or nominee should contact them
themselves.

If possible, the reason for withdrawal (e.g. adverse events, intercurrent
illness, illness progression, inability to adhere, inability to attend
regularly for treatment or assessment) should be ascertained. This
information will be passed on to the other relevant members of the team and
the trial manager (TM). The centre leader will ensure that every effort is
made to obtain the primary outcome measures and the Clinical Global
Impression (CGI) change score [49] from participants who drop out of
treatment as soon as this occurs, even if they are not dropping out of the
trial follow-up itself.

The centre leader or nominee will also ascertain whether consent is withdrawn
from further trial treatment only or from both trial treatment and follow-up
and in the latter case, whether the participant has given permission to
retain data collected before treatment withdrawal for use at final analysis.


Participant withdrawal of consent to research follow-up

If a participant withdraws consent for research (RN) follow-up during the
trial, the centre leader or nominee should be informed on the same day, if
possible. The centre leader or nominee will then contact the participant to
find out why the participant wishes to withdraw from research follow-up, if
they are willing to give a reason. The centre leader or nominee will also
determine whether the participant has given permission to retain data
collected before withdrawal for use at final analysis, or whether this
information should be destroyed. No data from the latter participant will be
used in analysis.


Loss to follow-up

Permission will be sought from the Office of National Statistics (ONS) in
England and the Information and Statistics Division (ISD) in Scotland, to
track all participants randomised using NHS numbers. If a participant is lost
to follow-up, the participant's GP will be contacted in the first instance,
and if the participant has moved from the area, ONS (or ISD) will be
contacted for details of the participant's new GP. This will only occur if
the participant has given explicit consent (as detailed on the consent form)
to allow this.

In all these situations the centre leader should inform the general
practitioner and any referring doctor that their patient has withdrawn from
either the trial or the trial treatment.


Measures of treatment compliance/adherence

The SSMC doctor will record how many clinic outpatient sessions were
attended, and how many were not attended during the 52 weeks by reviewing the
medical notes.

If the participant has been receiving supplementary therapy, the therapist
will record how many sessions/part sessions out of 15 were attended;
whether they were face-to-face or telephone consultations and the durations
of each session attended. At the end of therapy, the therapist will also
score how well the participant adhered to the general therapy approach.


Modification of trial treatment

Trial treatments will only be modified with the advice of the TSC, having
been advised by the DMEC that a particular treatment arm is causing a
consistent pattern of deterioration, or if there is another obvious and
significant clinical necessity. The MREC will also need to approve any change
in treatment.


Additional therapy after the trial

Participants who are judged to require further therapy after their
involvement in the trial has been completed, will be offered additional
therapy. The choice of additional therapy will be agreed by the participant,
clinic doctor and relevant therapist, and will start after the final
follow-up interview (52 weeks after randomisation into the trial).


Absence of a therapist

There will be occasions throughout the course of the trial when a therapist
is absent due to annual leave, sickness, maternity leave or resignation. In
these instances treatment delivery will be modified in order that a
participant's therapy and the trial may continue uninterrupted. Three
contingency plans have been devised to allow for a flexible approach to
tackling this situation when it arises.


Therapy from a nearby centre

Local centre cover is delivered by a PACE therapist of the same discipline
working in a nearby PACE centre.


Distant combined therapy

Distant therapy is delivered by a PACE therapist of the same discipline,
whereby the therapist will conduct some visits face-to-face and the remainder
by telephone. The participant at the same time may also be treated by a local
cross-cover PACE therapist.


Local cross-cover therapy

Cross-cover therapy is delivered by a PACE therapist of a different
discipline, whereby the cross-cover therapist learns a second PACE therapy to
a competent level. They are supervised both by a distant centre PACE
therapist of the appropriate discipline and a local therapist of the same
discipline providing emergency assistance and assessment in case the patient
has an intercurrent problem (e.g. pulls a muscle during GET).


Recruitment of a new therapist

In the case of resignation or maternity leave, the collaborating centre will
seek to recruit a replacement therapist as quickly as possible.

It is recognised that there is a shortage of therapists working in the NHS
and for this reason, the recruitment of staff of alternative appropriately
qualified disciplines may also be considered. For example, an exercise
physiologist may be recruited in place of a physiotherapist to deliver GET.
There have been two randomised controlled trials of GET for CFS/ME provided
by exercise physiologists, with positive outcomes [23,50]. In these instances
the therapist will operate as a 'physiotherapy assistant' to a supervising
physiotherapist. Similar alternative disciplines and supervision arrangements
may also be considered for APT and CBT.


Changes to consent process

If a participant is to receive treatment from a therapist of either a
different centre or a different discipline, the participant will give
additional informed consent once it is clear that they understand this and
are willing to receive their treatment in this way.


Assessments and Procedures

Assessments

All participants will usually be assessed at the hospital. Those participants
who cannot attend clinic will be offered home assessments (or failing this
assessment by telephone or by post). Before the second and consequent RN
assessments, self-rated measures will be posted to the participant prior to
the visit and checked for completion at assessment by the RN. If a
participant becomes too tired or ill to continue with the assessment, they
will be offered the opportunity to complete the assessment on another day,
within the next seven days.

Because we do not think it practically possible for the RN to remain blind to
treatment group allocation, we will not attempt to achieve this. All our
primary and secondary outcomes are therefore either self-rated or objective
in order to minimise observer bias. Participants who drop out of treatment
will be assessed for outcomes as soon as possible, rather than waiting for
the normal follow-up.

When the participant does not attend a research interview, the RN should send
the self-rated questionnaires to the participant's home address, with a
stamped addressed envelope. If questionnaires are not received back within a
week, the RN should arrange to visit the participant at home and oversee
completion of the questionnaires. If necessary, only the primary outcomes and
the CGI [49] (to assess deterioration) should be the minimum completed.


Long term follow-up

Permission will be sought from the participant to be contacted annually for
follow-up information regarding the participant's health and employment
status. The participant will also be invited to remain in contact so that the
results may be disseminated to them once published.


Measures

Primary outcome measures - Primary efficacy measures

Since we are interested in changes in both symptoms and disability we have
chosen to designate both the symptoms of fatigue and physical function as
primary outcomes. This is because it is possible that a specific treatment
may relieve symptoms without reducing disability, or vice versa. Both these
measures will be self-rated.

The 11 item Chalder Fatigue Questionnaire measures the severity of
symptomatic fatigue [27], and has been the most frequently used measure of
fatigue in most previous trials of these interventions. We will use the
0,0,1,1 item scores to allow a possible score of between 0 and 11. A positive
outcome will be a 50% reduction in fatigue score, or a score of 3 or less,
this threshold having been previously shown to indicate normal fatigue [27].

The SF-36 physical function sub-scale [29] measures physical function, and
has often been used as a primary outcome measure in trials of CBT and GET.
We will count a score of 75 (out of a maximum of 100) or more, or a 50%
increase from baseline in SF-36 sub-scale score as a positive outcome. A
score of 70 is about one standard deviation below the mean score (about 85,
depending on the study) for the UK adult population [51,52].

Those participants who improve in both primary outcome measures will be
regarded as overall improvers.

Secondary outcome measures - Secondary efficacy measures
1. The Chalder Fatigue Questionnaire Likert scoring (0,1,2,3) will be used
   to compare responses to treatment [27].
2. The self-rated Clinical Global Impression (CGI) change score (range 1
   - 7) provides a self-rated global measure of change, and has been used
   in previous trials [45]. As in previous trials, we will consider scores of
   1 or 2 as a positive outcome ("very much better" and "much better") and
   the rest as non-improvement [23].
3. The CGI change scale will also be rated by the treating therapist at
   the end of session number 14, and by the SSMC doctor at the 52-week
   review.
4. "Recovery" will be defined by meeting all four of the following
   criteria: (i) a Chalder Fatigue Questionnaire score of 3 or less [27],
   (ii) SF-36 physical Function score of 85 or above [47,48], (iii) a CGI
   score of 1 [45], and (iv) the participant no longer meets Oxford criteria
   for CFS [2], CDC criteria for CFS [1] or the London criteria for ME [40].
5. The Hospital Anxiety and Depression Scale scores in both anxiety and
   depression sub-scales [38].
6. The Work and Social Adjustment scale provides a more comprehensive
   measure of participation in occupational and domestic activities [33].
7. The EuroQOL (EQ-5D) provides a global measure of the quality of life [39].
8. The six-minute walking test will give an objective outcome measure of
   physical capacity [31].
9. The self-paced step test of fitness [43].
10. The Borg Scale of perceived physical exertion [44], to measure effort
   with exercise and completed immediately after the step test.
11. The Client Service Receipt Inventory (CSRI), adapted for use in CFS/ME
   [31], will measure hours of employment/study, wages and benefits received,
   allowing another more objective measure of function.
12. An operationalised Likert scale of the nine CDC symptoms of CFS [1].
13. The Physical Symptoms (Physical Health Questionnaire 15 items(PHQ15)) [35].
14. A measurement of participant satisfaction with the trial will also be
   taken at 52 weeks [53].


Adverse outcomes

Adverse outcomes (score of 5–7 of the self-rated CGI) will be monitored
by examining the CGI at all follow-up assessment interviews [49]. An
adverse outcome will be considered to have occurred if the physical
function score of the SF-36 [28] has dropped by 20 points from the
previous measurement. This deterioration score has been chosen since it
represents approximately one standard deviation from the mean baseline
scores (between 18 and 27) from previous trials using this measure
[23,25]. Furthermore, the RN will enquire regarding specific adverse
events at all follow-up assessment interviews.


Predictors
1. Sex
2. Age
3. Duration of CFS/ME (months)
4. 1 week of actigraphy [18] (as initiated at visit 1 with the research
   nurse)
5. Body mass index (measure weight in kg and height in metres)
6. The CDC criteria for CFS [1]
7. The London criteria for myalgic encephalomyelitis [40]
8. Presence or absence of "fibromyalgia" [41]
9. Jenkins sleep scale of subjective sleep problems [37]
10. Symptom interpretation questionnaire [34]
11. Preferred treatment group
12. Self-efficacy for managing chronic disease scale [32]
13. Somatisation (from 15 item physical symptoms PHQ sub-scale) [35]
14. Depressive disorder (major and minor depressive disorder, dysthymia by
   DSMIV) (from SCID) [30]
15. The Hospital Anxiety and Depression Scale (HADS) [38] combined score
16. Receipt of ill-health benefits or pension
17. In dispute/negotiation of benefits or pension
18. Current and specific membership of a self-help group (specific question)

Process variables
1. Step test of fitness [43]
2. Borg Scale of perceived physical exertion [44]
3. The symptom interpretation questionnaire [34]
4. Exercise and activity scale
5. PHQ symptom sub-scale
6. HADS scale combined score

Therapeutic input
1. At each RN assessment participants will be asked what other treatments
   they have been receiving (e.g. complementary and alternative therapies,
   prescribed and over-the-counter medicines).
2. The strength of the therapeutic alliance will be measured by the
   therapy integrity rating scale by an independent and blinded observer [53].
3. The differentiation of the supplementary therapies will be measured
   blind to treatment group by an independent observer [53].


Plausibility of therapy

After the first treatment session, all participants will be asked to fill in
a brief measure of how plausible their treatment appears to them.


Economic costs

The CSRI [42] will retrospectively record service utilisation for the six
months prior to the baseline assessment, for the period between baseline and
24 weeks, and then for the period from 24 weeks to 52 weeks. A comprehensive
range of services will be included so that in addition to being able to
determine the resource implications to the NHS, we will also have information
on the impact that treatment has on other parts of the care system as well as
on informal carers. The ability to engage in employment, education and work
in the home are frequently affected by CFS/ME and the CSRI will collect data
on these activities. Service use will be valued by attaching appropriate unit
costs from national sources (e.g. Netten et al, 2003 [54]) as well as
intervention costs specifically calculated for the study.


Adverse Events

Adverse events (AE) are any clinical change, disease or disorder experienced
by the participant during their participation in the trial, whether or not
considered related to the use of treatments being studied in the trial.


Serious Adverse Events (SAEs)

A Serious Adverse Event will be defined according to usual clinical trial
definitions and will be reported to the appropriate authorities in the
standard manner. If there is any doubt in the minds of the RN and the centre
leader as to whether the AE is a serious AE, the centre leader will obtain a
second opinion from one of the PIs.


Serious Adverse Reactions (SARs)

A Serious Adverse Reaction can be defined as: An SAE that is considered to be
a reaction to one of the supplementary therapies or a drug prescribed as part
of SSMC.


Reporting serious adverse events and reactions (SAEs and SARs)

In the event of an adverse event (AE), the centre leader or nominee will
judge the seriousness of the event, the relationship to a trial supplementary
therapy or SSMC prescribed treatment, clinical severity and the expectedness
of the event. All SAEs must be reported by the RN to the SSMC doctor (or SSMC
doctor to the RN), centre leader or nominee (e.g. another centre leader),
and the trial manager immediately the RN or SSMC doctor learns of the SAE,
regardless of the relationship to trial treatment. Reporting of SAEs and SARs
will be carried out according to normal regulatory requirements.


Non-serious adverse events and reactions

Non-serious adverse events or reactions will be assessed by the RN at each
follow-up assessment interview. A risk assessment has been undertaken, and we
have concluded that the therapies are of low risk to participants.
Non-serious adverse events will be reported according to the usual regulatory
requirements.


Follow-up after adverse events

After an SAE or SAR, a decision will be made by the centre leader as to
whether the participant should be withdrawn from either their randomised
treatment or from the trial, or need an alteration in their SSMC.
Arrangements will be made by the centre leader for further assessment and
management as required. Advice from the participant's GP, other health
professionals or relevant local authorities will be sought for any instance
of an SAE or SAR where further external advice is required. The RN will
provide the centre leader and TM with a one month follow-up report on all
SAEs and SARs. Further monthly reports should be provided in the absence of
resolution. These reports will be communicated to the DMEC and MREC via the
TM or trial statistician, and by the RN to the local Research and Development
(R&D) office.


Safety of participants

There is a discrepancy between patient organisation reports of the safety of
CBT and GET and the published evidence of minimal risk from RCTs. Surveys by
Action for M.E. of its members suggest that people becoming worse with these
treatments is caused by either rigidly applied programmes that are not
tailored to the patient's disability, or by improperly supervised programmes
[13-15]. PACE treatment manuals minimize this risk by being based on mutually
agreed and flexible programmes that vary according to the patient's response.
The RN will also carefully monitor for any adverse effects of the treatments.


Policy for deteriorating participant or one who drops out of treatment

The following policy will be enacted by the centre leader for any participant
who is considered, or considers themselves, to be deteriorating, or has
dropped out of treatment. The centre leader or delegated professional will
undertake a detailed clinical assessment, at home if necessary, following
which they will be offered appropriate help.


Recruitment, randomisation and retention

The right of the patient to refuse to participate in the trial without giving
reasons must be respected. Those recruiting and randomising participants will
rigorously maintain a position of equipoise and employ explanations that are
consistent with this [55]. All the participating clinicians regard all the
four treatments as potentially effective and are of the view that most
patients seen will accept randomisation if it is fully and openly explained.
Some patients are initially sceptical about treatment effectiveness but are
willing to accept any of these recommended treatments as long the treatment
is appropriately explained and delivered. Therefore, we do not anticipate a
difficulty either in acceptability of the proposed treatments, with
recruitment into the trial, or acceptance of randomisation. We emphasise that
we make this statement based on our having completed six trials of treatment
for CFS/ME. After the patient has entered the trial, the clinic doctor must
remain free to give alternative treatment to that specified in the protocol,
at any stage, if he/she feels it to be in the best interest of the patient.


Compliance

The trial will be conducted in compliance with the Declaration of Helsinki,
the trial protocol, MRC Good Clinical Practice (GCP) guidance, the Data
Protection Act (1998), the Multi-centre Research Ethics Committee (MREC) and
Local Research Ethics Committees (LREC) approvals and other regulatory
requirements, as appropriate. The final trial publication will include all
items recommended under CONSORT.


Sponsor

The main sponsor is Barts and the London, Queen Mary School of Medicine and
Dentistry.

Name of person/s authorised to sign the final protocol and protocol
amendments for the sponsor
* Chair of the Trial Steering Committee, Professor Janet Darbyshire.
* Professor Stephen Stansfeld (on behalf of the Sponsor).
* The three principal investigators.


Research Ethics Approval (MREC)

Ethical approval for the PACE trial was given by the West Midlands MREC
(reference number MREC/02/7/89). Local REC approvals have been sought and
obtained as required.


Indemnity

Each centre taking part in the trial will seek local approval and indemnity
through their NHS R&D department. As an automatic consequence of this, local
NHS indemnity will apply to the PACE trial. Details of local indemnity
arrangements can be obtained through each centre's NHS R&D department.


Analyses

Assumptions

The existing evidence does not allow precise estimates of improvement with
the trial treatments. However the available data suggests that at one year
follow up, 50 to 63% of participants with CFS/ME had a positive outcome, by
intention to treat, in the three RCTs of rehabilitative CBT [18,25,26], with
69% improved after an educational rehabilitation that closely resembled CBT
[43]. This compares to 18 and 63% improved in the two RCTs of GET [23,24],
and 47% improvement in a clinical audit of GET [56]. Having usual rather
than specialist medical care allowed 6% to 17% to improve by one year in two
RCTs [18,25]. There are no previous RCTs of APT to guide us [11,12], but we
estimate that APT will be at least as effective as the control treatments of
relaxation and flexibility used in previous RCTs, with 26% to 27% improved on
primary outcomes [23,26]. We propose that a clinically important difference
would be between 2 and 3 times the improvement rate of SSMC.


Power analyses

Our planned intention to treat analyses will compare APT against SSMC alone,
and both CBT and GET against APT. Assuming alpha=5% and a power of 90%, we
require a minimum of 135 participants in the SSMC alone and APT groups, 80
participants in the GET group and 40 in the CBT group [57]. However these
last two numbers are insufficient to study predictors, process, or
cost-effectiveness. We will not be able to get a precise estimate of the
difference between CBT and GET, though our estimates will be useful in
planning future trials. As an example, to detect a difference in response
rates of 50% and 60%, with 90% power, would require 520 participants per
group; numbers beyond a realistic two-arm trial. Therefore, we will study
equal numbers of 135 participants in each of the four arms, which gives us
greater than 90% power to study differences in efficacy between APT and both
CBT and GET. We will adjust our numbers for dropouts, at the same time as
designing the trial and its management to minimise dropouts. Dropout rates
were 12 and 33% in the two studies of GET [23,24] and 3, 10, and 40% in the
three studies of rehabilitative CBT [18,25,26]. On the basis of our own
previous trials, we estimate a dropout rate of 10%. We therefore require
approximately 150 participants in each treatment group, or 600 participants
in all. Calculation of the sample size required to detect economic
differences between treatment groups requires data of cost per change in
outcome, which is not currently available.


Unblinding

All research and therapy staff and participants are unblinded to treatment
allocation of individual participants. Therefore there will be no need for
unblinding during the trial. The one exception is the trial statisticians who
are blind to treatment allocation (coded A, B, C, D), as will be the DMEC, in
order to take actions on the basis of the unblinded data alone.


Analysis plan

A full Analysis Strategy will be developed, independently of looking at the
trial database, and before undertaking any analysis. This paper summarises
the analysis plan.


Primary analyses of efficacy

The primary analysis will be pragmatic, based on intention to treat, and will
utilise all available follow-up data from all randomised participants. The
primary binary outcomes of response on the fatigue and physical function
sub-scales (comparing proportions with categorical adverse deterioration with
this scale as well) and both and a combined response with will be analysed by
logistic regression adjusted for centre with contrasts for:
(1) APT vs. SSMC alone,
(2) APT vs. CBT,
(3) APT vs. GET,
(4) Trend across SSMC alone, APT, and CBT/GET combined,
(5) CBT vs. SSMC alone,
(6) GET vs. SSMC alone.

Participants not followed to one year will be classed as non-responders
unless they show a consistent pattern of outcome across assessments at 10,
24, and 39 weeks or whenever the last assessment is obtained.


Secondary analyses of efficacy

The secondary continuous outcomes will be analysed by repeated measures
analysis of variance using a linear mixed model with AR(1) covariance
structure, and including centre, depressive disorder, CDC and London criteria
and baseline values as covariates. The same contrasts as those specified for
the primary outcomes will be extracted. A summary measure, the area under the
curve, will also be reported.

A secondary, per protocol, analysis restricted to participants who complete a
minimum of 12 weeks of treatment (representing the mid point in therapy
time), will also be performed.

Further secondary sensitivity analyses will be used to assess the robustness
of conclusions for missing primary outcomes; these will employ repeated
binary outcomes, multiple imputation, and imputation analysing all possible
outcomes [58].

Loss to follow-up, departures from randomised treatment protocols, and the
prevalence of serious adverse events, will be reported at 13, 26, 39, and 52
weeks from randomisation.

Results from all analyses will be summarised as differences between percentages
or means together with 95% confidence limits (CL). The significance level for
all analyses of primary outcome variables will be P=0.05 (two-sided); for
secondary outcome variables, P=0.01 (two-sided)  unless profiles of response can
be specified in advance.

Prior to writing the Analysis Strategy a consensus will be reached on the
profiles of response for each secondary outcome within each of the four
treatment groups.


Predictions and process of treatment

Associations between post-treatment outcomes and both predictor and process
variables (including demographic, illness duration, and other putative
clinical indicators) will be examined using multiple linear and logistic
regression modelling techniques, including a limited examination of
interactions both amongst pairs of predictors and between predictors and
treatment groups. We anticipate that the sample size will be sufficient to
identify important general predictors from a random-split, training set of
two thirds (~400), with partial validation in the remainder, used as a test
set. Shrinkage techniques (to allow for over-optimism in variable selection)
will be applied in the development of a prognostic model to be applied to
participants outside the trial.


Economic analyses

The main economic evaluation will be a cost-effectiveness analysis conducted
from a societal perspective, examining comprehensive costs (treatment and
service costs plus lost productivity) and the two primary efficacy measures
(fatigue and physical function). Cost-effectiveness acceptability curves will
be plotted as necessary. A supportive cost-consequences analysis will be
conducted, examining comprehensive costs alongside all (primary and
secondary) efficacy measures. To inform special interests, evaluations will
also be conducted from the perspectives of the NHS, and also by using utility
scores in the cost-effectiveness analysis (computed from either the EQ-5D
[39] or the WSAS [33], there being arguments for and against each as the
basis for health-related quality of life measurement).


Monitoring

The principal investigators, centre leaders and participants will permit
trial-related monitoring, audits, ethics committee review and regulatory
inspections by providing direct access to source data/documents.


Independent overseers

The Data Monitoring and Ethics Committee (DMEC) will advise on the frequency
of reviews of the data on the basis of accrual and event rates.

The role of the independent Trial Steering Committee (TSC) is to provide
overall supervision for the trial and safeguard its integrity. Executive
authority for the continuation of the trial lies with the TSC.


Confidentiality

All data collected will be regarded as confidential and securely stored.


Quality assurance and quality control

Quality assurance and control will be ongoing throughout the trial.


Therapists' compliance with treatment manuals

Therapist compliance with treatment manuals will be monitored in two ways.
1) All therapists will receive a minimum of monthly telephone individual
supervision sessions, and face-to-face group and individual supervision at
least four times a year, depending on supervisory needs. All therapy sessions
will be video/audio-recorded. Some recordings will be used by
trainers/supervisors to provide feedback to therapists on competence and
treatment fidelity, which will happen particularly in the first few months of
a therapist starting to treat participants. Any significant deviations from
the manual will be noted and feedback given to the therapist. Therapist
competence will be measured by the relevant therapy leaders. Therapists will
be allowed to treat trial participants once they have been approved as
competent. 2) Two recorded sessions per therapist will be randomly chosen and
assessed blindly and independently by an assessor to assess adherence to
manual defined therapy.


SSMC doctors' adherence with SSMC manual

All SSMC doctors will receive training in use of the SSMC manual. All SSMC
sessions will be audiorecorded. Some recordings will be used by centre
leaders (using other centre leaders when the centre leader is providing SSMC)
to provide feedback to doctors on competence and treatment fidelity, which
will happen particularly in the first few months of a doctor starting to
treat participants. Any significant deviations from the manual will be noted
and feedback given to the doctor. Two recorded sessions per doctor will be
randomly chosen and assessed blindly and independently by an assessor to
assess adherence to manual defined treatment. In addition, this will be
particularly done for any doctor who routinely sees participants more than
five times in the twelve months of the study.


Participant non-adherence with treatment

Participant non-adherence with treatment will be measured both by recording
attendance and by therapist ratings of adherence to therapy.


Database quality

The senior data manager will be responsible for checking the quality of the
Trial Master Database (TMD), and will send local centre data managers query
forms as necessary.


Data Monitoring and Ethics committee

Reports to DMEC and the main analysis itself (as far as possible) will be
compiled blind to allocated treatment. DMEC reports will simply label
treatments as A, B, C or D. DMEC may request unblinding only if they have
serious concerns about any of the treatments. The unblinding would be handled
by a third statistician independent of the TMG. The DMEC can recommend
premature closure of the trial to the TSC. The circumstances for this need to
be agreed by the DMEC and TSC, but we suggest the only likely scenario is if
one of the trial treatments is shown to cause significant and consistent
deterioration in a significant number of participants (to be quantified at
the meeting of the DMEC). If one treatment arm does show consistent and
reliable evidence of causing serious adverse reactions in participants, then
consideration of closing that particular arm of the trial will be given. The
DMEC will be asked to keep a close eye on any consistent pattern of
deterioration of participants.


Discussion

The PACE trial will be the largest randomised trial of available treatments
for CFS/ME. It will provide important information about efficacy, adverse
events, cost-effectiveness, process and predictors. This will inform
patients, their carers, healthcare providers and commissioners which
treatments are most useful for which patients, and provide information
regarding the essential process of both recovery and improvement from CFS/ME.


Current Study Status

The PACE trial opened to recruitment in March 2005.


List of Abbreviations

AE Adverse Event

AfME Action for M.E.

APT Adaptive Pacing Therapy - in this protocol the abbreviation 'APT'
refers to Adaptive Pacing Therapy given with Standardised Specialist Medical
Care

CBT Cognitive Behaviour Therapy - in this protocol the abbreviation 'CBT'
refers to Cognitive Behaviour Therapy given with Standardised Specialist
Medical Care

CFS Chronic fatigue syndrome

CFS/ME Chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy
- Official term for the illness as described in the 'Working group report
to the Chief Medical officer' (2002) and the MRC RAG report (2003)

CMO Chief Medical Officer for England

CRF Case Report Form

CSO Chief Scientist's Office for Scotland

CTU Clinical Trials Unit

DM Data Manager

DMEC Data Monitoring and Ethics Committee

DH Department of Health

DM Data Manager

DWP Department for Work and Pensions

ELCMHT East London and City Mental Health Trust

GCP Good Clinical Practice

GET Graded Exercise Therapy - in this protocol the abbreviation 'GET' refers
to Graded Exercise Therapy given with Standardised Specialist Medical Care

ISD Information and Statistics Division

ISRCTN International Standard Randomised Controlled Trial Number

LREC Local Research Ethics Committee

ME Myalgic encephalomyelitis/encephalopathy

MRC Medical Research Council

MREC Multi-centre Research Ethics Committee

ONS Office for National Statistics

PACE Pacing, graded Activity and Cognitive behaviour therapy: a randomised
Evaluation

PI Principal Investigator

PCL Patient Clinic Leaflet

PIN Participant Identification Number

PIS Participant Information Sheet

PTM Participant Treatment Manual

R&D Research & Development - also referred to as NHS R&D

RN Research Nurse

SAE Serious Adverse Event

SAR Serious Adverse Reaction

SL&M South London & Maudsley NHS Trust

Sponsor Individual/organisation responsible for the initiation, management/
financing of a clinical trial

SSMC Standardised Specialist Medical Care

SUSAR Suspected Unexpected Serious Adverse Reaction

TCMF Trial Centre Master File

TM Trial Manager

TMD Trial Master Database

TMG Trial Management Group

TSC Trial Steering Committee


Competing interests

PDW has done voluntary and paid consultancy work for the Departments of
Health and Work and Pensions and legal companies and a re-insurance company.
MCS has done voluntary and paid consultancy work for government and for legal
and insurance companies. TC has done consultancy work for insurance
companies, is the author of Coping with Chronic Fatigue published by Sheldon
Press and co-authors Overcoming Chronic Fatigue with Mary Burgess published
by Constable and Robinson. RW and JD have no competing interests to declare.


Authors' contributions

PDW, MCS and TC are the co-principal investigators, conceived the study and
developed the design of this trial. RW is one of the trial statisticians and
participated in the design of the study. JD is the trial manager and
coordinator and contributed to trial design and protocol development. All
co-authors read and approved the final article.


Acknowledgements

General Information

This document describes the PACE trial, which was designed in collaboration
with Action for M.E. and funded by the Medical Research Council (MRC), the
Department of Health (DH), the Department for Work and Pensions (DWP) and the
Scottish Chief Scientists' Office (CSO) and provides information about
procedures for entering patients into it. Representatives of each of these
funding bodies are members of the Trial Steering Committee (TSC) and
therefore have contributed to the design of the study, the decision to submit
the manuscript and have approved this manuscript.

This paper should not be used as the protocol for executing the study, and is
not the complete protocol considered to be ethically satisfactory by the
relevant MREC, having been subject to shortening and revision to enhance
communication for publication. Neither the protocol nor the therapy manuals
should be used as aide-memoires or guides for the treatment of other
patients; every care was taken in its drafting, but corrections or amendments
may be necessary. These will be circulated to investigators in the trial, but
centres entering patients for the first time are advised to contact the trial
manager at St Bartholomew's Hospital, London to confirm they have the most up
to date version. Clinical problems relating to this study should be referred
to the relevant centre leader or one of the investigators.

All members of the trial management group (see below) participated in the
design of the study. The treatment leaders (see below) led the treatment
manuals' design, in collaboration with the principal investigators and aided
by the first wave centre therapists (see below). Other contributors to
treatment design included Action for M.E., Dr Lucy Clark, Helen Chubb,
Vincent Deary and Dr Kathy Fulcher. In addition to the TSC, the Data
Monitoring and Ethics Committee (DMEC) also contributed to the design of the
study. The memberships of these committees at the time of preparing this
manuscript are detailed below. The authors thank Professors Tom Meade,
Anthony Pinching and Simon Wessely for advice about design and execution.


Trial Steering Committee (TSC)

The Trial Steering Committee (TSC) is responsible for the independent
oversight of the progress of the trial, investigation of serious adverse
events, and determining the future progress of the trial in the light of
regular reports from the DMEC. The TSC is composed of:

Professor Janet Darbyshire (Chair),

Professor Jenny Butler (occupational therapist),

Professor Patrick Doherty (physiotherapist),

Dr Stella Harris (patient representative),

Dr Meirion Llewelyn (consultant physician in infectious diseases), and

Professor Tom Sensky (liaison psychiatrist and CBT therapist).

Observers include:

Professor Mansel Aylward (previously of DWP),

Mr Chris Clark (Action for M.E.),

Peter Craig (Scottish Executive),

Dr. Moira Henderson (DWP)

Susan Lonsdale (DH) and

Dr Sarah Perkins (MRC),

Professor Stephen Stansfeld (Queen Mary University of London, on behalf of
the sponsor).

Dr Alison Wearden (Principal Investigator of the FINE trial, an MRC funded,
sister study to PACE also researching CFS/ME).

Other members include the three investigators, the trial statisticians, and
the trial manager (secretary to the committee).

Membership has been approved by the MRC.

Previous members/observers include:

Dr Robin Buckle (MRC)

Professor Clair Chilvers (R&D, DH)

Data Monitoring and Ethics Committee (DMEC)

The Data Monitoring and Ethics Committee (DMEC) is independent and
responsible for monitoring progress of the trial and serious adverse events
and reactions. The DMEC will meet annually or more often if the chair
determines a reason for doing so, and provide a trial progress report at the
end of each meeting which will be sent to the TSC. The DMEC is composed of:

Professor Paul Dieppe (chair),

Dr Charlotte Feinmann (liaison psychiatrist) and

Professor Astrid Fletcher (epidemiologist).

Trial Management Group (TMG)

The Trial Management Group (TMG) will be responsible for the day-to-day
running and management of the trial. It is composed of:

* The three principal investigators
1. Professor PD White, Professor of Psychological Medicine, Centre for
   Psychiatry, Wolfson Institute of Preventive Medicine, Bart's and the
   London, Queen Mary School of Medicine and Dentistry, Department of
   Psychological Medicine, St Bartholomew's Hospital, London, EC1A 7BE.
2. Professor MC Sharpe, Professor of Psychological Medicine and Symptoms
   Research, School of Molecular and Clinical Medicine, Symptoms Research
   Group, Royal Edinburgh Hospital, Edinburgh, EH10 5HF.
3. Professor T Chalder, Professor of Cognitive Behavioural Psychotherapy
   Academic Department of Psychological Medicine, Guy's, King's and St
   Thomas' School of Medicine, Weston Education Centre, Cutcombe Road, London
   SE5 9RJ

* All centre leaders and co-leaders
1. Dr D Wilks
2. Professor S Wessely
3. Dr M Murphy
4. Dr BJ Angus
5. Professor T Peto
6. Dr E Feldman
7. Dr G Murphy
8. Hazel O'Dowd

* 4 treatment leaders (Jessica Bavinton, Mary Burgess, Diane Cox, Gabrielle
  Murphy, Lucy Clark and Helen Chubb)
* 2 health economists (Martin Knapp and Paul McCrone)
* Trial statisticians (Rebecca Walwyn and Tony Johnson)
* Chris Clark (for Action for M.E.) or a nominated deputy
* Julia DeCesare, Trial Manager
* Alison Wearden (observer for FINE trial)
* Sandy Smith, Senior Data Manager/Senior Research Secretary and secretary for
  the TMG


First wave therapists involved in piloting the therapies

Vincent Deary (CBT)

Nicola Dyer (GET)

Sally Ludlum (APT)

Louise Mason (APT)

Bella Stensnas (CBT)

Claire Topfer (GET)

Tracey Turner (GET)

Sally Wagner (APT)

Sue Wilkins (CBT)

Giselle Withers (CBT)



Figure captions

Figure 1 - Tables
Table 1: Flowchart of trial design
http://www.biomedcentral.com/content/figures/1471-2377-7-6-1.jpg


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(c) 2007 BioMed Central Ltd.

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Date:    Tue, 3 Apr 2007 12:45:25 -0400
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: The epidemic of vitamin D deficiency

The epidemic of vitamin D deficiency.

J La State Med Soc. 2007 Jan-Feb;159(1):17-20; quiz 20, 55.

Faiz S, Panunti B, Andrews S.

Ochsner Medical Center, USA.

PMID: 17396471


A 37-year-old woman was referred to our endocrine clinic for management of
her long-standing hypothyroidism. Her main complaints were muscle aches and
pains that started about a year ago. The symptoms progressed to generalized
muscle weakness. She described difficulty in getting out of her chair and
in climbing stairs. She had an extensive work-up done by her neurologist
and rheumatologist, including nerve-conduction studies and a muscle biopsy.
The evaluation was normal, and she was diagnosed with fibromyalgia.

She had gastric bypass surgery in 1998 and lost 150 pounds since the
operation. She also has had lactose intolerance and a compression fracture
without trauma. Her weight was 314 pounds. She had proximal muscle
weakness. The rest of her physical examination was normal. Serum laboratory
values are listed in Table 1. Based on the laboratory values, she was
diagnosed as having severe vitamin D deficiency. She was started on 50,000
IU of vitamin D2 (Ergocalciferol) once a week for 6 months. Now her 25
hydroxyvitamin D level is 40 ng/mL, and her muscle strength has improved.

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Date:    Tue, 3 Apr 2007 12:47:04 -0400
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Office management of chronic pain in the elderly

Office management of chronic pain in the elderly.

Am J Med. 2007 Apr;120(4):306-15.

Weiner DK.

Division of Geriatric Medicine, Department of Medicine, University of
Pittsburgh, Pittsburgh, Penn, USA. dweiner pitt.edu

PMID: 17398221


Chronic pain plagues older adults more than any other age group; thus,
practitioners must be able to approach this problem with confidence and
skill. This article reviews the assessment and treatment of the most common
chronic nonmalignant pain conditions that affect older adults--myofascial
pain, generalized osteoarthritis, chronic low back pain (CLBP),
fibromyalgia syndrome, and peripheral neuropathy.

Specific topics include essential components of the physical examination;
how and when to use basic and advanced imaging in older adults with CLBP; a
stepped care approach to treating older adults with generalized
osteoarthritis and CLBP, including noninvasive and invasive management
techniques; how to diagnose and treat myofascial pain; strategies to
identify the older adult with fibromyalgia syndrome and avoid unnecessary
"diagnostic" testing; pharmacological treatment for the older adult with
peripheral neuropathy; identification and treatment of other factors such
as dementia and depression that may significantly influence response to
pain treatment; and when to refer the patient to a pain specialist.

While common, chronic pain is not a normal part of aging, and it should be
treated with an emphasis on improved physical function and quality of life.

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Date:    Wed, 4 Apr 2007 13:53:26 -0400
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Coping with fibromialgia: Usefulness of the Chronic Pain  Coping Inventory-42

Coping with fibromialgia: Usefulness of the Chronic Pain Coping Inventory-42.

Pain. 2007 Mar 30; [Epub ahead of print]

Garcia-Campayo J, Pascual A, Alda M, Gonzalez Ramirez MT.

Department of Psychiatry, Miguel Servet University Hospital, Avda Gomez
Laguna 52, 4D, 50.009 Zaragoza, Spain; University of Zaragoza, Spain.

PMID: 17400387


There are few studies on coping with fibromyalgia (FM). The aim of the
present study was to assess the usefulness of a Spanish version of the
Chronic Pain Coping Inventory-42 (CPCI-42) in patients with FM.

A random sample (N=402) of patients with FM was obtained from the
Fibromyalgia Association of Aragon, Spain. Patients were assessed with the
CPCI-42, the Fibrofatigue Scale (FFS), the EuroQol-5D (EQ-5D), and the
Hospital Anxiety and Depression Scale (HADS).

The psychometric properties of the CPCI-42 were valid and factor analyses
supported the eight-factor structure described in patients with chronic
pain. Illness-focused coping strategies (i.e., guarding, resting, and
asking for assistance) were strongly correlated with each other, positively
correlated with disability and depression, and negatively correlated with
quality of life, indicating construct validity. Seeking social support was
weakly correlated with any other scale or outcome, confirming it belongs to
a different group of coping strategies. The wellness-focused group of
coping strategies was the most incoherent group. Task persistence
correlated with illness-focused strategies and negative outcomes,
indicating that it should be included in the illness-focused group.
However, other wellness-focused strategies, including relaxation, exercise,
and coping self-statements, were correlated with each other, negatively
correlated with depression, and positively correlated with quality of life.

Future research directions and clinical implications are discussed.

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Date:    Thu, 5 Apr 2007 13:16:17 -0400
From:    "Ellen Goudsmit <egoudsmit hotmail.com> via Co-Cure Moderator"
Subject: RES: An Alternative Strategy to Manage Fatigue in Chronic Fatigue Syndrome

Running head: PACING TO MANAGE CHRONIC FATIGUE SYNDROME


Pacing: An Alternative Strategy to Manage Fatigue in Chronic Fatigue Syndrome

Ellen M. Goudsmit                   Sandra Howes

London, UK


Ellen Goudsmit is a Chartered Health Psychologist, Sandra Howes is editor
of the ME and CFS References


Abstract
This article describes pacing, a strategy to help people with chronic
fatigue syndrome (CFS) to manage their energy and reduce exertion-related
increases in symptomatology.   Pacing recognises the plateau effect
described in the literature, and offers an alternative to graded activity
and graded exercise therapy (GET). We discuss the evidence supporting the
use of pacing, and its limitations.



Pacing: An Alternative Strategy to Manage Fatigue in Chronic Fatigue Syndrome.

             Recent recommendations for the management of CFS have focused
on two interventions, cognitive-behaviour therapy (CBT) and graded
activity/exercise therapy (GET), (Chambers, Bagnall,  Hempel, &
Forbes,  2006;  Reid, Chalder, Cleare, Hotopf, & Wessely,  2006).  Both
these approaches are based on the cognitive-behavioural model of CFS, which
posits that the symptoms are exacerbated and perpetuated by a combination
of inactivity and the physiological consequences of stress (Burgess, 2006;
Fulcher & White, 1997). However, surveys conducted by patients groups, as
well as studies assessing the effect of graded exercise, have indicated
that the strategy of gradually increasing activity levels is not always
effective and can lead to exacerbations in fatigue and other symptoms
(e.g., Black & McCully, 2005). The following article describes a strategy
for those patients who are either not able to increase their activity
levels, or for whom this approach would be inappropriate.

             The concept known as pacing was originally developed for
patients with myalgic encephalomyelitis (ME).  The cardinal symptom of this
disease is severe muscle fatigue following minimal exertion with a delay in
the recovery of muscle power after exertion ends (Dowsett & Welsby, 1992;
Ramsay, 1988, p.31).  Since it was first described by Goudsmit in 1989, the
strategy has also been adopted by people with CFS, a syndrome which shares
many of the features of ME (Goudsmit, Stouten, & Howes, 2006).  Initially,
details were disseminated via factsheets and magazines published by support
groups, but in recent years, information has also been available online
(e.g., Goudsmit, 2004).  So far, the feedback has been highly
encouraging.  For example, several surveys conducted during this time frame
showed  that patients regard pacing as more helpful than CBT, GET,
medication for pain and sleep, and a number of other orthodox and
complementary treatments (e.g. CFIDS Association, 1999; Action for M.E.,
2001).  There is also growing evidence that it is being accepted and
recommended by medical professionals (Nijs, Meeus, & de Meirleir, 2006;
Saidi & Haines, 2006; Van Houdenhove, 2006), whilst a controlled trial
indicated that pacing is useful in limiting deconditioning and reducing
levels of  fatigue (Wallman, Morton, Goodman, Grove,  & Guilfoyle, 2004).
Moreover, two programmes which included pacing as part of a
multi-dimensional approach revealed marked reductions in fatigue and
notable improvements in mood and overall health  (Goudsmit, 1996; Thomas,
Sadlier, & Smith, 2006).

Basic Guidelines
             The basic principle behind pacing is that patients should
remain as active as possible while avoiding over-exertion (Goudsmit, 2004).
Although a gradual increase in activity levels is permitted, the rule is
that they should stop when the initial mild fatigue turns into a more
unpleasant sensation, or where arms or legs begin to feel weak. Most
patients will experience these symptoms fairly quickly after commencing an
activity, but it is not unusual for some reactions to be
delayed.  Depending on where they are and what kind of activity triggered
the symptoms, the patient may choose to respond either by resting, or if
the fatigue is localised, by switching to an activity which uses a
different muscle group.

             Mental activities such as reading, speaking on the telephone
and using the computer are covered by the same rule, as is dealing with
stress. In practice, pacing means that patients should plan their day to
include plenty of time for rest and relaxation.  There is no need to divide
up minor tasks, but it is often helpful to restrict the number of demanding
or stressful activities to one a day. The remainder of that day can then be
spent doing less exhausting tasks, or resting, depending on how they
feel.  After a few weeks, most individuals will know from experience how
they tend to respond to various activities and what they can manage per day
without exacerbating their condition.

             Some patients find it helpful to keep a diary, especially in
the initial stages of the illness. This should include details of
activities and symptoms, as well as sleep quality, new foods added to the
diet and any event that was perceived as particularly difficult or
stressful. We recommend that patients then rate the past 24 hours on a
scale from 1, (ill, in bed all day) to 10 (well) as shown in appendix
1.  As most relapses do not occur at random, a diary can help identify the
various triggers, and monitor the effect of pacing and other coping
strategies.

             Once a person has a basic idea of what they are able to
tolerate, they can make provisional plans for the days or weeks ahead, as
long as they respond to any symptoms as they occur.  As variables such as
concurrent infections, the menstrual cycle, stress and even the weather can
affect how a person feels on a given day, we do not encourage patients to
stick to pre-determined schedules, or to set goals and targets. In our
view, patients require a flexible approach which allows them to adjust
their activities in order to avoid over-exertion, and to deal with the
effects of other physical, emotional or environmental factors influencing
their health. There are only two scenarios where we advocate that patients
should pace themselves on the basis of time, rather than symptoms. The
first situation where individuals should use external aids is to avoid
visual disturbances. While muscle fatigue and malaise are noticed fairly
quickly, it often takes longer to become aware of  'tired eyes'.
Accordingly, we recommend that a kitchen timer be used when reading or
using a computer, and to rest for five minutes every quarter or half an
hour, until it is clear how much the patient can tolerate. The second
scenario where it is helpful to time oneself is during any task which
requires a significant degree of concentration.  This is because many
patients find it difficult to gauge the effect of mental exertion and any
reactions to 'stress' are frequently delayed. Until patients have an idea
how these kind of activities affect them, they should play it safe and take
regular breaks.

             While this version of pacing is arguably the least complicated
and intrusive strategy available to patients who wish to manage their
energy levels, it doesn't suit everyone.  One of the most common problems
reported to us is the reluctance to stop an activity before it has been
completed. This is perhaps the main reason why at least in the initial
phase of the illness, many continue to operate well beyond their limits.
There are also individuals who push themselves because they do not
understand the relationship between their symptoms and exertion, or because
they wish to adopt a fighting attitude and perceive adaptation as a sign of
weakness. Others have difficulties with the self-discipline required, and
simply prefer a more structured programme, such as CBT and graded activity.

             As the illness improves, patients will experience less
weakness and fatigue, which should encourage them to gradually increase
their activity levels. If operating within the new limits does not trigger
an adverse reaction, we suggest that they switch to a GET-based programme,
to help build up their fitness. However, since pacing does not prevent
people from becoming aware of an increase in tolerance levels, there is no
need to test one's limits every few days and risk an unnecessary
exacerbation in symptoms.

Pacing and Switching
             As a result of experience and the research on post-exertional
fatigue (e.g., Paul, Wood, Behan,  & Maclaren, 1999), we now also recommend
an additional strategy which we have called  'pacing and switching'. Pacing
and switching means changing activities to avoid tiring specific muscle
groups. For instance, if a person has been walking, the advice is to stop
before, or at the first signs of fatigue and to switch to something
involving different muscles, e.g. reading, watching TV, washing or
ironing.   Patients can continue this new activity for a while, then either
rest, revert back to what they were doing before, or switch to something
new.  Using this approach, it may be possible to further reduce the
duration and severity of post-exertional fatigue and hence extend the
energy available for everyday tasks. Like the original version, pacing and
switching is determined by how one feels, not by pre-determined plans and
goals. It can be combined with the original version, or practiced on its
own, depending on circumstances and personal preferences.

Pacing versus Graded Exercise
There are a number of different programmes which encourage graded increases
in activity. The version recommended by the team at King's College Hospital
requires patients to alternate between activity and rest periods, and find
a baseline where they feel they can keep up their agreed level even on a
bad day. They are then advised to "introduce a slight increase in activity;
keep it up till it gets easier, then move up again... Small, consistent
steps are the key... You will improve by small degrees over a period of
time, or you may have to decrease some of your activities, gradually
introduce rest in some areas of our life" (Deary, 2006a).  If patients
experience more fatigue and muscle ache, they are assured that "this is the
body's normal response, it does not mean a relapse of your illness.
Providing that everything has been done gradually, and you have not been
over ambitious, this should not be too painful, and it should pass after a
few weeks at most"  (Deary, 2006b).

             1. Theoretical differences.
             Graded exercise-based programmes assume that the fatigue
reported by people with CFS is largely perpetuated by physical
deconditioning, sleep disturbance and/or psychological distress (Clark &
White,  2005; Fulcher & White 1997). Conversely, pacing makes no
assumptions about aetiology but adopts a precautionary principle, in this
case, that the symptoms may reflect ongoing disease.  This view is
supported by several studies which found no clear correlation between
deconditioning and the symptoms of CFS (Bazelmans, Bleijenberg, van der
Meer,  & Folgering, 2001; De Becker,  Roeykens,  Reynders,  McGregor, & De
Meirleir, 2000, Sargent,  Scroop, Nemeth, Burnet,  & Buckley, 2002) and by
the growing evidence of pathology in a subset (see below). In fact, where
fitness levels do not appear to play a major role, the rationale behind GET
seems counter-intuitive. If minor exertion triggers fatigue, why should
gradually increasing the exertion have the reverse effect?

             The emphasis on inactivity is also difficult to reconcile with
some of the clinical features  documented in the literature on fatigue
syndromes.  For instance, ME tends to affect the most often used muscles,
so that in right-handed people, the muscles in the right hand and arm are
generally weaker than those on the left (Ramsay, 1983). Similarly, studies
on both ME and CFS have identified  specific deficits in cognitive
function, which are difficult explain in terms of fatigue, malaise or an
overall 'mental dulling' (DeLuca,  Christodoulou, Diamond,  Rosenstein,
Kramer, & Natelson, 2004;  Smith, 1991).

             There is also a further difference between the strategies.
Pacing aims to reduce symptoms both in the short and long term, while those
promoting graded activity expect patients to tolerate weeks of illness and
pain. There is no evidence at the moment that one approach is superior to
the other, but the existence of two different ways of managing limited
energy  offers patients a choice and means they can experiment to find a
strategy which suits their personality, circumstances as well as their
symptoms.

             2.  Practical differences.
             As noted above, GET encourages patients to stick to the
predetermined schedules even if they are feeling tired and unwell. Some
therapists allow individuals to stay at the same level for a few days, some
may suggest increasing the periods of rest (Deary, 2006a), but only in
exceptional cases, such as during a concurrent illness, are people allowed
to stop (Bleijenberg, Prins, & Bazelmans, 2003). This is based on the
principle that patients need to build up their fitness and that there's no
gain without pain.  In contrast, pacing requires patients to listen to
their body and to stop when they begin to feel unwell. This is, in fact,
the most important difference between the two approaches. While there are
clear overlaps between pacing and activity programmes such as that promoted
by Kings' College Hospital  both advocate finding one's limits and
alternating activity and rest - the issue which separates them is not how
much patients should do, but when they should stop.

             3. Financial differences.
             Pacing  is a strategy which requires no specialist training. A
GP or practice nurse can explain the basic rules, and if required, assist
patients who have problems in identifying their baseline. A review
appointment may be useful to check that the condition has begun to
stabilise, and that the patient is functioning at a level they can
tolerate. For the more severely affected, pacing can be included in a
multi-disciplinary treatment programme or other intervention which also
provides medical care, emotional support, counselling, and dietary advice
(e.g., Goudsmit, 1996, Thomas et al., 2006).

Other Versions of Pacing.
Balancing Rest and Activity (time-based pacing)
             This version has been included in some patient literature, and
appears to require the splitting of activities to avoid over-exertion.  For
example, the booklet on pacing produced by Action for M.E. (2004a) notes:
"When you are doing a specific task, such as preparing a meal, it's very
tempting to try to complete it in one burst of activity. Instead, split the
activity into a series of small stages, with periods of rest and relaxation
in between" (p. 17). When establishing a baseline, patients are advised to
be very cautious.  "If you think that you can carry out an activity for 20
minutes, try reducing your activity time by five minutes to 15 minutes (75%
of 20 minutes). The aim would then be to maintain 15-minute blocks of
activity interspersed with rest/relaxation periods throughout the day. An
even simpler way is to set your baseline at about 50% of what you think you
can do on an average day. Split each activity up with 5  10 minute rest
breaks"  (p. 24).

             Once the illness has stabilized, patients are encouraged to
increase the number or duration of activities.  However, instead of
interpreting adverse reactions as a sign of over-exertion, Action for M.E.
takes the same line as GET-based programmes.  The booklet states: "you are
likely to notice a temporary increase in stiffness or fatigue when
increasing your activity levels. This is normal and your body will need a
few days to adjust and adapt. However if your fatigue and other symptoms
continue for a week or longer this might indicate that you have increased
the activity too quickly".

             Theoretically, it is not clear on what evidence this protocol
is based. One paper available online referred to the experience with
chronic pain and the 'envelope theory' (Action for M.E., 2004b, p. 1, 2).
In practice, the latter involves matching perceived energy with expended
energy, although Jason and his colleagues do not require patients to
operate below their capabilities, nor do they advocate that they tolerate
an increase in symptoms for a week before adjusting their routine
(Friedberg & Jason, 1998; Jason, Tryon, Taylor, King, Frankenberry, &
Jordan, 1999).

             Action for M.E.'s version of  pacing differs from the original
in a number of ways. It is primarily based on time rather than the presence
of symptoms, it requires more planning than the original strategy,  the
rest is pre-emptive rather than recuperative, and because the patients have
to estimate what they can tolerate, many may spend a much longer period
operating below their maximum level of functioning.  In contrast, the
original version encourages patients to live as normal a life as possible,
but to let their body tell them when they need to rest. Symptoms such as
weakness and malaise are not regarded as 'normal', and accordingly, it is
recommended that individuals adapt their activities immediately, rather
than wait for a week. However, it is consistent with the envelope
theory  and the version of pacing as described by Friedberg & Jason (1998).

             Part of Action for M.E.'s programme resembles a strategy first
put forward by Collinge (1994). He named it the "fifty-percent solution"
because patients are advised to do only 50 per cent of what they think they
are capable of (p. 81).  They are then asked to monitor the impact of their
activities for two days. If they relapse, they have to reduce their
assessment; if they remain stable,  they can repeat the process.  According
to Collinge, this strategy allows patients to spend half the available
energy and invest the other half in their body's healing process.  So far,
there has been no study of this approach to assess its efficacy.

             Like Action for M.E., Campling & Sharpe (2000) recommend that
patients use pacing to stabilise the illness but that they proceed to
increase their activity levels, as in GET,  in order to improve.  An
initial exacerbation of symptoms is considered "completely normal", and
they advocate that patients try to tolerate the symptoms for a week before
amending their plans.  While there is no published evidence that this
combination is superior to either strategies alone, it is important that
patients have different options, and since the version of graded activity
advocated by Campling and Sharpe is comparatively flexible and realistic,
it may be more acceptable to patients than other forms of GET.

Adaptive Pacing Therapy (APT)
             This is currently being assessed in a MRC funded trial.
However, as there is no information about APT in the public domain, it is
not possible to evaluate this programme.

The Scientific Aspects of Pacing
             The reports of fatigue following minimal exertion and the
prolonged delay in the recovery of muscle strength are consistent with
research by Paul et al., (1999). They found objective evidence of a loss of
muscle strength lasting at  least 24 hours, showing that this aspect of ME
is not merely a result of a perceptual error or the misinterpretation of
normal physiological phenomena. Further evidence of post-exertional fatigue
was provided by Jason, Melrose, Lerman, Burroughs, Lewis, King, &
Frankenberry (1999) who used time series regression to assess the
relationships between perceived exertion, quality of sleep and symptoms.
They found a close association between current energy expenditure and
fatigue, but also a correlation  between fatigue and the energy expended
one hour, five hours and seven hours previously.  To obtain more objective
data, Sisto, Tapp,  LaManca, Ling, Korn,  Nelson, & Natelson (1998)
assessed activity levels over a period of 14 days using waist-worn
accelerometers.  Following a treadmill test, they observed a 10%  reduction
in activity levels in the CFS group compared to the sedentary controls, and
this was accompanied by an  increase in the number of daily rests. They
also identified a second reduction in activity levels a few days after the
test, consistent with the subjective reports of delayed reactions to
exertion, and again, this was accompanied by an increase in
rest.  Overall,  the total daily activity levels remained relatively
stable, suggesting that many of these patients were successfully pacing
themselves, and there was no evidence of 'boom and bust' prior to the test.
Their findings contrast with those of Lapp (1997)  who reported that the
majority of his patients felt worse after exercise, and that 22% of  them
were still in relapse  when the study ended after 12 days. As he did not
provide detailed data on activity levels, it is unclear if these
individuals modified their behaviour after the test. It is also possible
that Lapp's patients were more severely affected or that they included a
greater proportion of subjects with ongoing disease.

             Research to explore the mechanisms underlying the phenomenon
of post-exertional fatigue has identified abnormal responses to exertion
affecting muscle function, the immune system, gene expression and brain
perfusion. For example, Lane, Barrett, Woodrow, Moss, Fletcher,  & Archard
(1998) reported that 37% of  patients with broadly-defined CFS had abnormal
lactate responses to exercise, and this was often associated with a
relative deficiency in mitochondria rich type 1 muscle fibres. The tissue
samples showed few effects of inactivity and only 10% of the 105 cases
had  muscle fibre atrophy. More recently, Sorensen, Streib, Strand, Make,
Giclas, Fleshner, & Jones (2003) revealed an increase in the complement
split product C4a, part of the immune response to foreign cells, six hours
after exercise. No significant differences from baseline or between groups
were observed for the cell-associated pro-inflammatory cytokines
interleukin-1ß, interleukin-6, tumour necrosis factor-a, and interferon-a
or the anti-inflammatory cytokine interleukin-10. However, an interesting
trend was observed: the CFS group means were elevated at 6 hours after
exercise for each of the pro-inflammatory cytokines, whereas the control
group means were decreased at the same time point.  Similarly, White, Nye,
Pinching, Yap, Power, Vleck,  Bentley,  Thomas, Buckland, & Parkin (2004)
found increases in concentrations of tumor necrosis factor-a in patients
with CFS, and this was evident both three hours and three days after
exercise. They also identified elevated concentrations of transforming
growth factor-ß  after the journey from home to the hospital, and these
remained high following exercise. The increased release of this
anti-inflammatory cytokine during a relatively normal activity was
unexpected  but may be of clinical significance.

             Further abnormalities have been reported  by Whistler, Jones,
Unger, & Vernon (2005) who  found differences between patients and controls
in ion transport and ion channel activity at baseline, which were
exaggerated after exercise, as evidenced by greater numbers of
differentially expressed genes. Also intriguing is the abnormal reaction to
exercise observed on SPECT (Goldstein, 1992). Scans from healthy
individuals tend to exhibit increased brain perfusion after
modest  exercise. However, when studying a person with CFS, Goldstein
documented significant decreases in perfusion in several areas of the brain
and the defects found at rest had become "aggravated".  Twenty-four hours
post-exercise, there was further evidence of hypoperfusion,  consistent
with anecdotal reports of  delayed reactions to exercise and the phenomenon
of post-exertional malaise.

             One controlled trial supporting the use of pacing assessed a
programme which also included medical care, emotional support and advice on
sleeping and avoiding stress (Goudsmit, 1996).  Over 80% of patients with
post-infectious fatigue syndrome reported feeling better and there were
significant differences between the treated patients and controls at six
months for fatigue, somatic symptoms and self-efficacy. Moreover, 23% of
the patients had improved to such a degree that they were discharged. The
small size of the sample means that this study requires replication, but it
should be noted that the improvements were comparable to those reported for
CBT, and that these were achieved in a clinical setting, rather than a
well-resourced research clinic.

             Another study examined the effect of gently increasing
activities such as walking, cycling or swimming every second day unless the
subject experienced a relapse or symptoms became worse (Wallman et al.,
2004). In those circumstances, sessions were either shortened or cancelled
and subsequent  sessions were reduced to a length that the patient regarded
as manageable. The programme improved resting systolic blood pressure, work
capacity, depression and performance on a cognitive test. However, while
91% of the participants  rated themselves as 'better' and no one felt that
it had made them worse, the reduction in physical fatigue scores failed to
reach significance and the increases in activity were similar to that
recorded by the relaxation/flexibility group who acted as controls.

             There is also evidence from several surveys which supports the
use of pacing. For example, of the 820 members of the CFIDS Association of
America who responded to a questionnaire, 71% rated pacing as helpful, and
none reported adverse effects (CFIDS Association, 1999). Conversely, 34.5%
rated GET as helpful but 28% noted adverse effects. In a British survey of
2338 patients, 89% rated pacing as helpful, 9% felt that it had made no
difference and 2% thought it had made them worse (Action for M.E., 2001).
In contrast, 34% regarded GET  as helpful, 16% reported no change while 50%
believed  that it had made them worse. None of the surveys gave a
definition of pacing but all preceded the publicity about the time-based
version, APT and 'pacing and switching' and it may therefore be assumed
that the views relate to earlier versions, such as those described by
Goudsmit (UK), and Collinge (USA). Finally, a 10-year follow-up report of
people who developed post-viral fatigue following an outbreak in 1984 found
that most were able to lead a near normal life by pacing themselves
(Levine, Snow, Ranum, Paul, & Holmes, 1997). In other words, many patients
had made significant improvements without graded exercise programmes and CBT.

It is worth noting here that the original version of pacing was not
conceived as a treatment or therapy for the illness as a whole and Goudsmit
has made no claims about the effects of this strategy on visual
disturbances, thermoregulatory abnormalities, sore throats, nausea, balance
problems and some of the other symptoms associated with ME and CFS.
Instead, she envisaged pacing as one component in a programme which would
also offer medical care, emotional support, dietary advice and
psychological interventions as required.  Although some studies have
assessed pacing alone and in combination with CBT, we wish to emphasize the
limitations of  this strategy, and accordingly suggest that without
psychological support and symptomatic treatment, any improvements are
likely to be limited (Friedberg & Krupp, 1994; Wallman et al., 2004;
Wright, Ashby, Beverley, Calvert, Jordan, Miles, Russell, & Williams, 2005).

Graded Exercise in Context
Given the heterogeneity of the population, and the differences in
circumstances, personality and phase of illness, it is difficult to
determine which strategy  is right for which patients.  Various reviews
have concluded that both GET and CBT appear to reduce fatigue and improve
physical functioning in a significant proportion of patients with CFS
(Chambers et al., 2006; Reid et al., 2006). Indeed, some regard it as the
most effective forms of treatment available, although  the results have
been far from consistent and many of the reported improvements have been
modest.

             One of the problems which makes it difficult to evaluate the
various treatments is the limited number of outcome measures used in some
of the trials.  For example, most studies do not   include an objective
measure of activity and it is therefore unclear if any of the improvements
can be attributed to the exercise regime.  The importance of such
information was demonstrated by Black, O'Connor, &  McCully (2005), who
studied six people with CFS and seven sedentary controls. Following a two
week baseline period, CFS subjects were asked to increase their daily
physical activity by 30% over baseline by walking a prescribed amount each
day for a period of four weeks. Although the patients were able to increase
their activity levels by an average of 28%, they reported an increase in
fatigue, muscle pain and overall mood disturbance. A more detailed analysis
of the data revealed that the increases in activity were restricted to the
first 4-10 days of  walking and that after this time, walking and total
activity counts decreased (Black & McCully, 2005). In their view
(Discussion ¶ 11),  "the inability to sustain target activity levels,
associated with pronounced worsening of symptomatology, suggests the
subjects with CFS had reached their activity limit."  Although it can be
argued that the targets were too ambitious and that the sample was too
small to draw firm conclusions, it shows the value of  including objective
measures to assess both progress and effectiveness.

             Another study which included an objective measure of activity
also failed to show a significant increase following GET (Prins,
Bleijenberg, Bazelmans, Elving, de Boo, Severens, van der Wilt, Spinhoven,
& van der Meer, 2001 as discussed by Van Essen &  De Winter, 2002, p. 57).
Indeed, there is as yet no evidence that programmes such as those promoted
by the teams at Kings' College Hospital (Deary, 2006a) and Nijmegen
(Bleijenberg et al., 2003) lead to significant  and sustained increases in
activity. In this context, it is worth noting a report by Friedberg (2002)
who followed one patient's progress for a period of 12 months.  From
baseline to treatment termination, the person's self-reported increase in
walk time from 0 to 155 minutes a week contrasted with a 10.6% decrease in
mean weekly step counts.  While the patient felt better, it appeared that
the improvement may have been due other factors, such the substitution of
stressful activities for more mood-enhancing ones, and a reduction in
job-related overtime.

             The often cited study by Fulcher & White (1997) revealed a
significant  reduction in mean levels of fatigue and an increase in
physical functioning but none of these measures had returned to normal and
there were no improvements for anxiety, depression and quality of sleep.
Moreover, there were no data showing that  people had increased their
activity levels after treatment.  In another British study, Wearden,
Morriss, Mullis, Strickland,  Pearson,  Appleby, Campbell, & Morriss (1998)
reported a 12% reduction in fatigue at 26 weeks and a 10% improvement in
functional work capacity at 12 and 26 weeks in those who completed the
programme. However, 37% of the patients dropped out, and again, there was
no information on post-trial activity levels.

             While GET is clearly helpful for a proportion of patients with
CFS, there is as yet no evidence that it is equally beneficial in those
patients with neurological and immunological abnormalities  (Lloyd,
Hickie,  Brockman,  Hickie, Wilson, Dwyer,  & Wakefield, 1993). Moreover,
studies of  CBT/GET conducted  in clinical settings have reported less
impressive outcomes than the published randomised, controlled trials,
highlighting  the need to evaluate all interventions in routine practice,
as well as research clinics (Akagi,  Klimas, & Bass, 2001; Quarmby, Rimes,
Deale, Wessely, & Chalder, in press).

             Since graded exercise assumes that there is no underlying
disease process causing the fatigue, it may be argued that it is not an
appropriate first line treatment for patients with
documented  abnormalities in the brain (Costa, Tannock, & Brostoff,  2005)
and muscle (McGarry, Gow, & Behan, 1994), and those with raised levels of
antibodies or evidence of immune activation (Innes, 1970; Landay, Jessop,
Lennette, & Levy,  2001; Lane, Soteriou, Zhang, & Archard, 2003).  However,
if people are avoiding activity due to fear or misinformation, if their
symptoms are not closely linked to exertion, or if they are well on the way
to recovery, then a rehabilitation programme which includes GET is likely
to be more beneficial than pacing and similar strategies.

Concerns about Pacing
             It has been argued that close monitoring of bodily changes may
intensify the perception and experience of symptoms (Dittner & Chalder,
2003).  While this may be applicable in a number of cases, it should be
noted that there is as yet no evidence that regular monitoring increases
the severity of fatigue or that it affects the course of the illness.
Moreover, it is important to differentiate between responding to symptoms
as one becomes aware of them, an inherent part of pacing, and constant
monitoring, which is unnecessary and should be discouraged.

             A further issue concerns the influence of anxiety and
depression, both of which may exacerbate CFS and undermine coping.  Pacing
is not appropriate for these conditions but that is no reason to reject it
as a strategy to help manage the exertion-related symptoms associated with
CFS and ME.

             A third concern is that without gradual increases in activity,
people will not improve (Straus, 2002; White, 2002). This view reflects a
lack of knowledge about pacing. By avoiding the symptoms caused by
over-exertion, people will feel less exhausted and have a greater sense of
control compared to those who have not yet learnt to pace themselves, or
who regularly exceed their limits. As well as reducing the number of
relapses, it also prevents the 'boom-bust' cycles reported in the
literature, and the symptoms caused by deconditioning.  Given the limited
evidence showing that GET leads to sustained increases in activity, and the
paucity of information regarding its effects on symptoms other than fatigue
and emotional distress, any claims that patients will not improve unless
they increase their activity levels should be interpreted with caution.

Conclusion
             Pacing is a management strategy to help patients with CFS
limit the number and severity of relapses and avoid at least some of the
complications of inactivity. It may be particularly useful for those who
are already operating near or at their maximum level of functioning, and
who cannot increase their activities beyond a certain point. It may also be
appropriate for individuals with neurological and immunological
abnormalities. Pacing therefore offers an alternative to GET and increases
the number of therapeutic options for what is a complicated and often
extremely disabling condition.



References

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Appendix

Diary
[Note: it is virtually impossible to replicate this diary in plain text
e-mail.  Please see http://www.co-cure.org/pacing.htm for a more
presentable version.]

  ActivitiesScore
Mondayam.  20 min cycling hospital. Fatigue. Dizzy. 20 min standing in
queue. Weak legs. pm relax. TV, write letter, ok. Sleep, fair. Mood good.6
Tuesdayam. Rest, relax. Wash hair, ok. pm nausea 3.00pm. rest, potter.
Diet. Tried sweet and sour meal, lunch. Sleep, fair. Mood good.6
Wednesdayam. Cycle 10 minutes hairdresser. Dizzy after a few minutes.
  pm. Relax. TV.  Read. Ok.   Sleep fair. Mood ok.7
ThursdayAm. Handwash, TV, relax. ok. Pm. vacuum two small rooms. Ok Relax.
Dinner, burger,  chocolate, cake. Cramps. Disturbed night. Mood ok.5
FridayAm. Nausea. Cramps. Rest in bed. pm. Potter. Fragile.
Better night. Mood ok. 4


Notes
             This simple diary takes very little time to complete but
provides a lot of useful information. While the patient is pacing her
activities well and there is no sign of  boom and bust,  minor lifestyle
changes may reduce or even avoid certain symptoms.    For example, cycling
and standing for 20 minutes is clearly beyond her limits and she needs to
take care about her intake of sugar and fats. The dizziness at the
hairdresser on Wednesday could be related to the position of the neck
during washing (ask to bend forward), or reflect exposure to the
airborne  chemicals from the  products used in the salon.

             The use of a diary allows the patient and GP to identify the
factors undermining the patient's state of health, particularly in the
early stage of the illness,  and the flexibility of pacing means that the
person can respond quickly to changing circumstances. This gives both a
sense of control and  limits the distress associated with
exacerbations.  Keeping a diary after the initial stage may help both the
patient and doctor to see the stabilisation of the illness and hopefully,
some improvement.


Acknowledgements.

We wish to thank all the patients, and Ms. Elaine Sturman MCSP for their
helpful comments on earlier drafts.

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Date:    Thu, 5 Apr 2007 17:23:41 -0400
From:    Fred Springfield <fredspringfield VERIZON.NET>
Subject: RES: Actuarial analysis of private payer administrative claims  data for women with endometriosis

Actuarial analysis of private payer administrative claims data for women
with endometriosis.

Journal: J Manag Care Pharm. 2007 Apr;13(3):262-72.

Authors: Mirkin D, Murphy-Barron C, Iwasaki K.

NLM Citation: PMID: 17407392


BACKGROUND: Endometriosis is a painful, chronic disease affecting 5.5
million women and girls in the United States and Canada and millions more
worldwide. The usual age range of women diagnosed with endometriosis is 20
to 45 years. Endometriosis has an estimated prevalence of 10% among women
of reproductive age, although estimates of prevalence vary greatly.
Endometriosis is the most common gynecological cause of chronic pelvic
pain, but published information on its associated medical care costs is
scarce.

OBJECTIVE: The aim of this study was to determine (1) the prevalence of
endometriosis in the United States, (2) the amount of health care services
used by women coded with endometriosis in a commercial medical claims
database during 1999 to 2003, and (3) the endometriosis-related costs for
2003, the most recent data available at the time the study was performed.

METHODS: This study was a retrospective review of administrative data for
commercial payers, which included enrollment, eligibility, and claims
payment data contained in the Medstat Marketscan database for approximately
4 million commercial insurance members. All claims and membership data were
extracted for each woman aged 18 to 55 years who had at least 1 medical or
hospital claim with a diagnosis code for endometriosis (International
Classification of Diseases, Ninth Revision, Clinical Modification
[ICD-9-CM] codes 617.00-617.99) for 1999 through 2003. Claims data from
1999 through 2003 were used to determine prevalence and health care
resource utilization (i.e., annual admission rate, annual surgical rate,
distribution of endometriosis-related surgeries, and prevalence of comorbid
conditions). The cost analysis was based on claims from 2003 only. Cost was
defined as the payer-allowed charge, which equals the net payer cost plus
member cost share.

RESULTS: The prevalence of women with medical claims (inpatient and/or
outpatient) containing ICD-9-CM codes for endometriosis was 1.1% for the
age band of 30 to 39 years and 0.7% over the entire age span of 18 to 55
years. The medical costs per patient per month (PPPM) for women with
endometriosis were 63% greater ($706 PPPM) than those of the average woman
per member per month ($433) in 2003; inpatient hospital costs accounted for
32% of total direct medical costs. Between 1999 and 2003, these women with
endometriosis who were identified by either inpatient and/or outpatient
claims had high rates of hospital admission (53% for any reason; 38% for an
endometriosis-related reason) and a high annual surgical procedure rate
(64%). Additionally, women with endometriosis frequently suffered from
comorbid conditions, and these conditions were associated with greater PPPM
costs of 15% to 50% for women with an endometriosis diagnosis code,
depending on the condition. Interstitial cystitis was associated with 50%
greater cost ($1,061 PPPM); depression, 41% ($997 PPPM); migraine, 40%
($988 PPPM); irritable bowel syndrome, 34% ($943 PPPM); chronic fatigue
syndrome, 29% ($913 PPPM); abdominal pain, 20% ($846 PPPM); and
infertility, 15% ($813 PPPM).

CONCLUSIONS: Women with endometriosis have a high hospital admission rate
and surgical procedure rate and a high incidence of comorbid conditions.
Consequently, these women incur total medical costs that are, on average,
63% higher than medical costs for the average woman in a commercially
insured group.

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------------------------------

Date:    Thu, 5 Apr 2007 17:29:54 -0400
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: A Combination of 6 Months of Treatment with  Pyridostigmine and Triweekly Exercise Fails to Improve Insulin-Like  Growth Factor-I Levels in Fibromyalgia, Despite Improvement in the  Acute Growth Hormone Response to Exercise

A Combination of 6 Months of Treatment with Pyridostigmine and Triweekly
Exercise Fails to Improve Insulin-Like Growth Factor-I Levels in
Fibromyalgia, Despite Improvement in the Acute Growth Hormone Response to
Exercise.

J Rheumatol. 2007 Apr 1; [Epub ahead of print]

Jones KD, Deodhar AA, Burckhardt CS, Perrin NA, Hanson GC, Bennett RM.

From the Schools of Nursing and Medicine, Oregon Health and Science
University, Portland, Oregon, USA.

PMID: 17407215


OBJECTIVE: People with fibromyalgia (FM) often have low insulin-like growth
factor-I (IGF-I) levels and a suboptimal growth hormone (GH) response to
acute exercise. As previous work had demonstrated a normalization of the
acute GH response to exercise with the use of pyridostigmine (PYD), we
tested the hypothesis that 6 months of PYD therapy plus supervised exercise
would increase IGF-I levels.

METHODS: Subjects with primary FM were randomized into 4 groups: (1)
PYD/exercise; (2) PYD/diet recall; (3) placebo/exercise; and (4)
placebo/diet recall. The dosing of PYD was 60 mg tid for 6 months. Resting
IGF-I levels were measured at baseline and after 6 months of treatment. In
addition the acute GH response to exercise at VO2 max was measured at
baseline and after treatment.

RESULTS: A total of 165 FM subjects (mean age 49.5 yrs, 5 male) were
entered and 154 (93.3%) completed the study. Six months of therapy (PYD
plus exercise or exercise alone) failed to improve the IGF-I levels. The
use of PYD 1 hour prior to exercise improved the acute GH response (4.54
ng/dl) compared to placebo (1.74 ng/dl) (p = 0.001) at the end of the
6-month trial. The acute GH response to exercise at baseline did not
correlate with IGF-I, age, depression, medications, estrogen status, or
obesity.

CONCLUSION: A combination of triweekly supervised exercise plus the daily
use of PYD for 6 months failed to increase IGF-I levels in patients with
FM, despite the confirmation that PYD normalizes the acute GH response to
strenuous aerobic exercise.

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------------------------------

Date:    Fri, 6 Apr 2007 15:24:32 -0400
From:    Fred Springfield <fredspringfield VERIZON.NET>
Subject: RES: Functional neuroimaging correlates of mental fatigue  induced by cognition among chronic fatigue syndrome patients and controls

Functional neuroimaging correlates of mental fatigue induced by cognition
among chronic fatigue syndrome patients and controls.

Journal: Neuroimage. 2007 Mar 3; [Epub ahead of print]

Authors: Dane B. Cook [a, b, *], Patrick J. O'Connor [c], Gudrun Lange [d,
e] and Jason Steffener [f]

Affiliations:
[a] Department of Veterans Affairs-William S. Middleton Memorial Veterans
Hospital, Madison, WI 53706, USA
[b] Department of Kinesiology, University of Wisconsin, Madison, WI 53706, USA
[c] Department of Kinesiology, University of Georgia, Athens, GA 30602, USA
[d] Department of Veterans Affairs-New Jersey Health Care System, East
Orange, NJ 07018, USA
[e] Department of Radiology, University of Medicine and Dentistry of New
Jersey Medical School, Newark, NJ 07103, USA
[f] Cognitive Neuroscience Division of the Taub Institute for Research on
Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY
10032, USA
[*] Corresponding author. 2000 Observatory Drive, Unit II Gym, Department
of Kinesiology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Fax: +1 608 262 1656.

Received 18 January 2007;
revised 12 February 2007;
accepted 13 February 2007.
Available online 3 March 2007.

NLM Citation: PMID: 17408973


The neural mechanisms underlying feelings of fatigue are poorly understood.
The primary purpose of the study was to use functional magnetic resonance
imaging (fMRI) to determine the association between feelings of mental
fatigue and blood oxygen level dependent (BOLD) brain responses during a
mentally fatiguing cognitive task.

Healthy, non-fatigued controls and chronic fatigue syndrome (CFS) patients
were included to determine the influence of chronic levels of fatigue on
brain responses. We hypothesized that mental fatigue would be significantly
related to brain activity during a fatiguing cognitive task but not during
either a non-fatiguing motor (finger tapping) or cognitive (auditory
monitoring) task.

Patients (n=9) and controls (n=11) completed a finger tapping task, a
simple auditory monitoring task and a challenging working memory task,
designed to induce mental fatigue, while undergoing fMRI. Fatigue was
measured prior to scanning and following each task during fMRI data collection.

Results showed that mental fatigue was significantly related to brain
activity during the fatiguing cognitive task but not the finger tapping or
simple auditory monitoring tasks. Significant (p</=0.005) positive
relationships were found for cerebellar, temporal, cingulate and frontal
regions. A significant (p=0.001) negative relationship was found for the
left posterior parietal cortex. CFS participants did not differ from
controls for either finger tapping or auditory monitoring tasks, but
exhibited significantly greater activity in several cortical and
subcortical regions during the fatiguing cognitive task.

Our results suggest an association between subjective feelings of mental
fatigue and brain responses during fatiguing cognition.

[Return to top]

------------------------------

Date:    Fri, 6 Apr 2007 18:42:05 -0700
From:    Co-Cure moderators <cocuremoderator QWEST.NET>
Subject: RES: D-Ribose article

Posted on behalf of a subscriber:


The following article is available free online at the moment in their sample
journal:

http://www.liebertonline.com/acm

Teitelbaum, JE., Johnson, C and Cyr, JS. The use of D-Ribose in
chronic fatigue syndrome and fibromyalgia: a pilot study. Journal of
Alternative and Complementary Medicine, 2006, 12, 9, 857-862.

D-Ribose is one of the nutrients recommended by Dr Paul Cheney in the 2006
DVD.


Abstract and link to PDF article:

http://www.liebertonline.com/doi/abs/10.1089/acm.2006.12.857?prevSearch=allfield%3A%28D-Ribose+in+CFS%29

[Return to top]

------------------------------

Date:    Sat, 7 Apr 2007 16:41:02 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: Press release: Alpha-Delta sleep in CFS

Source: Virus Weekly
Date:   April 10, 2007
URL:    http://www.newsrx.com/newsletters/Virus-Weekly/2007-04-10/430410200753RW.html
Ref:    This paper is available from the Co-Cure list archive,
        http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0703A&L=co-cure&P=R1872


Chronic Fatigue Syndrome
------------------------
Study results from Vrije University, Department of Human Physiology in the
area of chronic fatigue syndrome published

A report, "Defining the occurrence and influence of alpha-delta sleep in
chronic fatigue syndrome," is newly published data in The American Journal
of the Medical Sciences. According to recent research from Brussels, Belgium,
"Patients with chronic fatigue syndrome (CFS) present a disordered sleep
pattern and frequently undergo polysomnography to exclude a primary sleep
disorder. Such studies have shown reduced sleep efficiency, a reduction of
deep sleep, prolonged sleep initiation, and alpha-wave intrusion during deep
sleep."

(...)

--------
(c) 2007 NewsRx

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------------------------------

Date:    Sat, 7 Apr 2007 14:13:24 -0400
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Awareness and Perceptions of Fibromyalgia Syndrome: A  Survey of Southeast Asian Rheumatologists

Awareness and Perceptions of Fibromyalgia Syndrome: A Survey of Southeast
Asian Rheumatologists.

J Clin Rheumatol. 2007 Apr;13(2):59-62.

Arshad A, Ooi KK.

From the *Rheumatic Diseases Unit, Putra Specialist Center, Alor Star,
Kedah, Malaysia; and daggerDepartment of Rheumatology, Allergy and
Immunology, Jalan Tan Tock Seng, Tan Tock Seng Hospital, Singapore, Singapore.

PMID: 17414529


BACKGROUND:: Fibromyalgia syndrome (FMS) is a common but controversial
condition. There appears to be different level of belief of its existence
and awareness. We set out to explore the variations of perceptions and
awareness of this condition among rheumatologists from the Southeast Asia
(SEA) region.

METHODS:: One hundred eight rheumatologists from the participating
countries; 28 from Malaysia, 20 from Singapore, 26 from Thailand, 2 from
Brunei, and 42 from Indonesia were approached to participate in this survey
by answering specific questions regarding their beliefs in relation to FMS;
82% respondents from Malaysia, 100% from Singapore, 92% from Thailand, 100%
from Brunei, and 90% from Indonesia completed the questionnaires.

RESULTS:: Most rheumatologists (92.5%) from SEA believe that FMS is a
distinct clinical entity, and also this condition is considered an illness
rather than a disease. Eighty-seven percent rheumatologists from SEA
believe that FMS is a mixture of medical and psychological illness, 9%
believe that FMS is primarily a psychological illness, and 3% believe that
it is a medical illness. Only 60% of those in a university setting include
FMS in their undergraduate teaching. Eighty-five percent of the respondents
ordered blood tests to exclude other serious pathologic conditions, and
100% of the respondents from SEA countries also prescribed some form of
drugs to FMS patients.

CONCLUSION:: FMS is apparently seen worldwide. This study confirmed that
there was a variation of perceptions and knowledge of FMS among
rheumatologists from SEA countries. However, most rheumatologists agreed
that FMS is a distinct clinical entity with a mixture of medical and
psychological factors.

[Return to top]

------------------------------

Date:    Sat, 7 Apr 2007 14:36:09 -0400
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Fibromyalgia: Update on Mechanisms and Management

Fibromyalgia: Update on Mechanisms and Management
[Rheumatology Grand Rounds at Rush]

JCR: Journal of Clinical Rheumatology:Volume 13(2)April 2007pp 102-109

Clauw, Daniel J. MD

From the *Division of Rheumatology, Chronic Pain and Fatigue Research
Center, †Clinical and Translational Research, University of Michigan
Medical Center, Ann Arbor, Michigan.
 From Rheumatology Grand Rounds at Rush University Medical Center, Chicago,
IL, USA. Editors: Robert S. Katz, MD, and Joel A. Block, MD.

Reprints: Daniel J. Clauw, MD, Director, Chronic Pain and Fatigue Research
Center, University of Michigan Medical Center, Ann Arbor, Michigan 48109.
E-mail: dclauw med.umich.edu

PMID: 17414543


THE ACR CRITERIA FOR FIBROMYALGIA: THE GOOD AND THE BAD
The American College of Rheumatology criteria have been both bad and good
for fibromyalgia.1 When they were published in 1990, this is what we
thought fibromyalgia was: chronic widespread pain and the 11 of 18 tender
points. If this is your view of fibromyalgia, then fibromyalgia is really
no different than other rheumatic diseases like osteoarthritis or
rheumatoid arthritis or lupus-a discrete illness. In 1990, we also thought
that the tenderness was confined to certain areas of the body, or at least
more accentuated in certain areas of the body, which we refer to as tender
points. Finally, another misconception that exists to this day in many
people's mind is that psychological and behavioral factors are always
present in people with fibromyalgia and always make them worse.

A more contemporary view of fibromyalgia is that rather than being a
discrete illness, it is a part of a huge continuum of pain and somatic
syndromes. It happens to be what we, as rheumatologists, are most
comfortable calling it. But these individuals have pain throughout their
entire body that isn't due to damage or inflammation, and there's a great
deal of scientific evidence that this is one large spectrum of illness that
includes fibromyalgia, irritable bowel, and temporomandibular joint (TMJ)
syndrome-as well as a number of other conditions that I'll talk about
later. Even if we use the American College of Rheumatology (ACR) criteria
to diagnose fibromyalgia (i.e., on the basis of widespread tenderness and
pain), people don't just have tenderness and pain. They have a lot of other
somatic symptoms besides pain and tenderness. And, again, psychological and
behavioral factors only play negative roles in some individuals.

We also now know that the entire individual with fibromyalgia is tender,
and that there is nothing magical about tender points. These are merely
areas where everyone is more tender. But fibromyalgia patients are also
much more tender wherever you apply pressure, including areas previously
considered to be control points. In fact, in our research group, when
performing sophisticated imaging studies, we push on the thumbnail because
we found that the thumbnail is just as tender (relative to that same region
in a healthy control) as any of the tender points. Fred Wolfe was the first
to point this out. He suggested that we should abandon this old term that
used to be called control points and call them high-threshold tender
points; areas like the forehead and the thumbnail and the anterior tibial
region are just areas where all of us have a higher pain threshold.

These are many other problems with ACR criteria and specifically with
tender points. We didn't know any of this in 1990, so I'm not being
critical of the people who were involved in developing the ACR criteria
because they have been wonderful in standardizing research into
fibromyalgia. But we didn't know that tender points are actually not a very
good measure of tenderness. In 1997, Wolfe published an article where he
looked at some of the data that he collected in population-based studies.
He had found that the number of tender points an individual has is highly
correlated with the number of measures of distress-of anxiety, depression,
and distress.2 What he said in that article was that tender points are a
sedimentation rate for distress. Since then, our group and others have
shown that other more sophisticated measures of tenderness, such as where
you give people stimuli randomly when they can't anticipate what the next
stimulus is going to be, are just as abnormal in people with fibromyalgia,
but these are not at all related to the level of distress of the
individual.3 So people with fibromyalgia are indeed much more tender, or
they have what we would call a left-shift in their stimulus-response
function with respect to pressure. So the take-home message is that
fibromyalgia patients are much more tender even using more sophisticated
measures that are not confounded by distress. However, tender points are
not a very good measure of tenderness. Tender points are part a measure of
tenderness and part a measure of how anxious and depressed an individual is.

I might be the first author that I know of that's been able to get away
with writing a chapter in textbook regarding fibromyalgia without having an
illustration of a woman with 18 dots on it, because I think that the longer
that we highlight the ACR criteria and highlight these 18 areas of the
body, the longer physicians are going to think that there is something
uniquely wrong with those 18 areas of the body rather than realize that
this is a diffuse, central problem with pain processing. This gives an
inappropriate impression about the nature of fibromyalgia when you put
those 18 dots and they all happen to be located over muscle-tendon
junctions and people sort of think, Well, that's where the problem is,
rather than realizing that this is a problem in the central nervous system
with the way people are processing pain or sensory information. Our group
hypothesizes that this is actually a more global problem with sensory
processing, not just pain processing, because people with this spectrum of
illness are sensitive to a number of different types of stimuli rather than
just somatic pain.

I think one of the other disservices that the ACR criteria has done is that
they've deluded us into thinking that fibromyalgia occurs almost
exclusively in women. If you use the ACR criteria, 92% of the people in the
population who are identified as meeting those criteria are females. But if
you break down the criteria into the 2 elements, (1) chronic widespread
pain and (2) 11 of 18 tender points, women are only 1[1/2] times as likely
as men to have chronic widespread pain, but women are 11 times as likely as
men to have 11 of 18 tender points. So what we've done with the ACR
criteria is take an illness that is probably only about 1[1/2] times more
commonly in women and make physicians think that this occurs only in
females. This is similar to what we did a couple of decades ago when I was
trained as a rheumatologist, when we were taught that ankylosing
spondylitis only occurred in males. When that's what we were taught, then
we only thought of the diagnosis of ankylosing spondylitis in men, even
though later data showed that the prevalence of AS is very similar in men
and women.

The same thing happens now with women versus men in chronic pain. Men who
come in with the same exact symptoms and physical examination as women with
fibromyalgia are more likely to be labeled with regional pain syndromes
such as osteoarthritis, because if you do X-ray after X-ray (or worse yet
MRI after MRI) you will always find something wrong. I used to have a
diagnostic test called the X-ray jacket sign because when we went to the VA
clinic, they would pull the X-ray jackets on all patients (before the
X-rays were digitalized). I joked that if you could pull 10 consecutive
musculoskeletal X-rays out and none of them were abnormal, that was a
diagnostic test for fibromyalgia. And we had many men in the rheumatology
clinic that we were seeing who had been labeled as osteoarthritis or
chronic low back pain, who clearly had fibromyalgia. But the diagnosis
carried for years and years in their chart was a regional pain syndrome
such as osteoarthritis, even though there were inadequate radiographic
findings to support this, and they typically did not respond very well to
treatments for peripheral pain.

Then the last thing that people should be aware of with tender points, and
that is that 11 is a totally arbitrary number. Robert Katz has published
articles recently talking about how different types of criteria function
equally well. And he and I, and almost everyone in the fibromyalgia field,
agree that the ACR criteria should not be used in clinical practice to
diagnose fibromyalgia. They never were intended for that purpose. They were
intended to standardize research studies. And they don't function very well
at all when you use them in routine clinical practice.

Every subspecialist that I know, except perhaps radiologists and
pathologists, sees patients that was as rheumatologists call fibromyalgia
and has one or more names for the symptoms in the area of the body they are
responsible for. It is not until you realize the entirety of the problem,
like the pharmaceutical industry now does, that you understand that this is
one large problem that needs to be addressed in primary care, rather than
something that's just been bestowed upon us in rheumatology because we have
to deal with these fibromyalgia patients.

MECHANISMS IN FIBROMYALGIA
So to summarize, there's nothing wrong with thinking that fibromyalgia is a
discrete disorder. But I'm going to talk of it as being more of the end of
the continuum, or the way the pharmaceutical industry is viewing this right
now, which is that it is the prototypical central pain state, where people
can get pain and other somatic symptoms without having anything really
wrong in their peripheral tissues that would cause a nociceptive problem.

Regarding the underlying mechanisms in this spectrum of illness, we didn't
know in 1990 what we know now about pain sensitivity. In 1990, the thought
was that there were sort of 2 groups of people in the population: a small
group of people who were very tender and thus met criteria for
fibromyalgia, and the rest of the population, who had a normal pain
threshold. But in the last 15 or so years, there have been a number of
different studies of pain sensitivity in the population. And we now know
that pain sensitivity in the population occurs over a wide continuum, a
classic bell-shaped curve, just like almost any other physiologic variable.
We're also learning that genetics have a lot to do with where you are on
this continuum. I am quite comfortable saying that in 5-10 years we will
have gene chips that will have been developed that will predict with a
reasonable accuracy where people are on this bell-shaped curve, because
polymorphisms and a number of different genes that involve the breakdown
and metabolism of neurotransmitters involved in sensory transmission will
predict with a fair amount of accuracy where someone is going to sit on
this curve. And if you happen to be in the top quartile or tertile of that
bell-shaped curve, on the far right where you're very sensitive to pain,
you probably can develop pain without having any inflammation or damage in
your peripheral tissues; and that can either be regional or widespread pain.

So this is really the emerging notion of what's going on in these fields
like fibromyalgia, TMJD, and irritable bowel. People, because of a
combination of the genes they are born with and the environment that they
grew up in, move to the right end of this bell-shaped curve and can develop
pain and other somatic symptoms because of what's going on in their central
nervous system rather than because of any damage or inflammation in their
peripheral tissues.

The best work showing the genetic and familial nature of fibromyalgia has
been done by Lesley Arnold and her colleagues.4 They showed that if someone
has fibromyalgia, the risk of one of their first-degree relatives having
fibromyalgia is 8-fold greater. To put it in context, in lupus and
rheumatoid arthritis, the odds ratio is 2 to 3; and we think of those
diseases as being somewhat familial. But fibromyalgia is incredibly
familial. And one of the nice things about this study is that it somewhat
challenged an earlier notion that Jim Hudson, who was actually a coauthor
of this study, published in the mid 1980s where he called this an affective
spectrum, because he felt that depression and anxiety coaggregated strongly
with fibromyalgia. The new studies, which he was also involved in,
partially proved his theory, but the coaggregate between these disorders
and fibromyalgia is weaker than previously suggested by studies done
entirely in tertiary care centers. So there is a weaker coaggregation with
mood disorders genetically, whereas there is a very strong coaggregation
with other pain syndromes like fibromyalgia and irritable bowel syndrome
and TMJ syndrome, and other psychiatric disorders such as obsessive
compulsive disorder and bipolar disorder.

One of the best studies looking at the precise genetic cause of conditions
related to fibromyalgia was done by Luda Diatchenko and Bill Maixner at the
University of North Carolina.5 They looked at a large cohort of women who
were pain-free and followed them for 3 years to see who developed the TMJD
syndrome, and showed that how tender an individual was at baseline, and
polymorphisms in the COMT gene, predicted who went on to develop the TMJD
syndrome over the 3-year period. That's just one single polymorphism, and
there are a number of different polymorphisms that are probably playing a
role in pain.

There probably will be 20 or so genes that end up predicting with a
reasonable amount of accuracy where someone is on this continuum of pain
processing. But where I think it's going to be incredibly useful in 5 to 10
years is to figure out what drugs to give people who have this spectrum of
illness because if I see that one person might have developed fibromyalgia
because of an abnormality in catecholamine synthesis because of COMT or
ß-adrenergic receptors, then these individuals might respond very well to,
for example, a mixed reuptake inhibitor or low doses of a ß blocker.
Whereas individuals who have different polymorphisms might be more
responsive to drugs like pregabalin or gabapentin, or other classes of
drugs, which will be developed in the future, that act on other
neurotransmitters that either increase or decrease an individual's pain
sensitivity.

Given that nearly all illnesses are due to some combination of genes and
environment, we also are beginning to better understand the environmental
factors that seem to be important in triggering fibromyalgia. Most may be
acting as stressors. One stressor that is clearly capable of causing
fibromyalgia is to begin by having a peripheral pain syndrome (i.e., pain
due to damage or inflammation of peripheral tissues). I'm not sure what
percentage of rheumatologists are aware of this, but 20 to 25% of people
with RA, lupus, and ankylosing spondylitis, have comorbid fibromyalgia.6 I
see young and old rheumatologists who make the diagnosis of an autoimmune
disease and then hone in and inordinately focus their treatment on
autoimmunity. Every time that patient has pain or fatigue, we raise their
dose of immunosuppressives because we think that's what is causing their
pain and their fatigue. But if a quarter of the people with autoimmune
diseases have comorbid fibromyalgia, maybe they need a low dose of
amitryptiline or some aerobic exercise rather than a cytotoxic drug or 10
more milligrams of prednisone.

Another stressor that can trigger this spectrum of illness is infections.
Four different infections that have been shown in case-controlled studies
to trigger either fibromyalgia or chronic fatigue syndrome: Epstein-Barr
virus, parvovirus, Lyme disease, and Q fever.7 There are 2 studies
published in the Lancet showing that the common cold isn't capable of
triggering either chronic fatigue syndrome or fibromyalgia. Now, in almost
all of my talk, you could substitute the word IBS for fibromyalgia and give
the exact same talk, and it would be accurate. But this is one area where
fibromyalgia and IBS would differ. The infections that trigger irritable
bowel syndrome are virtually any infections that cause acute infectious
colitis-nearly all have been shown in case-control studies to lead to the
subsequent development of IBS. Likewise, a number of different
genitalurinary infections have been shown to be capable of triggering the
development of interstitial cystitis

So depending on where in the area of the body responsible for one of the
syndromes, different infections that attack that area of the body seem to
be capable of triggering it. But only about 4 to 7% of people with these
infections go on to develop fibromyalgia, IBS, or interstitial cystitis,
whereas the overwhelming majority of individuals that have these same
infections recover fully and go on to their baseline state of health. So,
again, it's probably some interplay between the genes the people are born
with and the infections that they get.
Physical trauma is another stressor that is capable of triggering the
development of fibromyalgia. But one of the fascinating things about this
is that this occurs much more frequently in some countries than others. In
Lithuania, motor vehicle accidents trigger almost no chronic regional or
chronic widespread pain; whereas in the United States, they trigger a fair
amount of it.8 It's not the patient's fault. It has little to do with the
insurance systems because this happens in no-fault and in other insurance
systems. And it probably doesn't even have much to do with the disability
and litigation systems. It may have more to do with what we as physicians
(and the healthcare system) lead people to expect what will or won't happen
after acute musculoskeletal trauma.

In Lithuania, when you come in after a motor vehicle accident, and you see
an emergency room physician, there is no expectation that there will be any
chronic symptoms after that; you are given a few days worth of
anti-inflammatory or analgesic medications, and told to go back to work. In
the United States and many other countries, we give people opioids, tell
them they might develop chronic pain, and tell them to rest. We haven't
learned our lesson from good research in conditions such as acute low back
pain, where we now know that the worst thing to do with someone with low
back pain is to make them expect they might develop chronic pain, and tell
them to stop moving and rest. So it may actually may be our health systems
and the expectations that we as physicians set up with our patients when
they come in with acute pain rather than being litigation or disability.

With respect to stressors, there's actually weak data that psychologic
stress and distress directly causes fibromyalgia. One of the fascinating
things is I'm always surprised, being a scientist, at how often my clinical
judgment ends up being wrong. When I was first doing research in
fibromyalgia, I, like many of you, was always smacked in the face by the
psychologic comorbidity that a lot of fibromyalgia patients come in and
express. But the data suggest that many types of psychologic stress don't
seem to trigger or worsen fibromyalgia. We were doing a study in
Washington, D.C., where we were beginning to work with a company that was
doing clinical trials in fibromyalgia, and they wanted to do more
innovative outcome measures of fibromyalgia patients. So we were having
fibromyalgia patients in Washington, D.C., wearing Palm pilots that beeped
5 times a day and they had to record their pain, their fatigue, their
stress levels 5 times daily. As is not unusual in research, some of the
best things that happen to you are serendipitous; and the 9/11 attacks on
the Pentagon happened right smack in the middle of the study. So we had
about 20 people who had been recording their pain, their fatigue, and their
other symptoms, before and after the Pentagon attack, miles away from where
all of these patients were living.

We expected that we would see pain, fatigue, and stress levels go sky high
in people with fibromyalgia after 9/11, but there was absolutely no change.
Karen Raphael was doing a population-based epidemiologic study in New
Jersey where she had collected baseline data in people right across the
river from the World Trade Center in New Jersey, and similarly found no
increase in symptoms.9 So you have to be very careful about attributing
emotional stress to the development of fibromyalgia. It likely is very
important what type of stress, and interpersonal stress may be much more
likely to exacerbate or trigger fibromyalgia than the type of stress seen
after 9/11.

Finally, war is another thing that triggers the development of this
spectrum of illness. The Department of Defense provides funding for our
research group and many others because of the recognition that after the
first Gulf War and, in fact, maybe after every war, one of the major
postdeployment health problems is the development of chronic pain, fatigue,
and what we would call either fibromyalgia, chronic fatigue syndrome, IBS,
etc.10


RELATIONSHIP BETWEEN NEUROBIOLOGICAL FACTORS AND PSYCHOLOGICAL, COGNITIVE,
AND BEHAVIORAL FACTORS
One of the most controversial questions in this illness is what is the
relationship between physiologic or neurobiologic factors and psychologic
and behavioral factors. If you do research in this area, you quickly
realize that the old dualist notion of organic versus functional illnesses
needs to be abandoned, because everything that is psychologic or behavioral
likely has neurobiologic and physiologic underpinnings, and psychologic and
behavioral factors play significant roles in even the most biologic of
illnesses. In fact, I think that one of the big tragedies regarding this
spectrum of illness is that 30 or so years ago, fibromyalgia was on had
equally poor credibility as a real disease with mental health disorders
such as bipolar disease, major depression, and schizophrenia. But now these
latter conditions are more credible than fibromyalgia, in large part
because scientific studies have shown that there are strong biologic
underpinnings to these illnesses. The research showing strong biologic
underpinnings is equally strong in this spectrum of illness, but most
physicians and the lay public are not yet aware of these findings. This
will likely change rapidly in the next few years as new drugs are approved
specifically for fibromyalgia, and the companies marketing these drugs will
do a thorough job of educating both physicians and patients about these
conditions.

Until then, though, these patients are shunned and inappropriately treated
in our current health care systems. Everyone is averting their eyes and
acting like they're not part of the problem here. But we are.
Rheumatologists don't want fibromyalgia. Gastroenterologists don't want
IBS. None of the subspecialties want this. So there never has been an
advocacy campaign like the psychiatrists and other mental health
professionals mounted to legitimize psychiatric conditions.

Having said that I'm not a dualist, it can actually be very helpful when
you're sitting across the examination room from a fibromyalgia patient, to
be a bit dualistic, and ask yourself how much social, cognitive,
behavioral, and psychological factors are playing a role in symptom
expression. Not all fibromyalgia patients are the same. Some of them
respond very well to a little bit of a tricyclic drug and a little bit of
education, and they never come back because they do fine. Others don't get
better no matter what we do. We did a study published in Arthritis &
Rheumatism a couple of years ago where we tried to develop subgroups based
on 3 different domains. One domain was neurobiological; that was how tender
people were using these more sophisticated measures of pressure pain
threshold. One domain was whether they were depressed or anxious. And then
the third domain was cognition, how they think about their pain. There are
2 particular cognitive patterns that are known to be very negative in pain.
One is catastrophizing, which means that people have a very negative,
pessimistic view of what their pain is and what it's doing to them. The
other is an external locus of control, which basically means that people
feel as though they can't do anything about their pain, so they can't
control their pain. This study that I referred to earlier looked at 97
patients that we had been seeing at Georgetown, and 50 of them fell into
the group we refer to as primary-care fibromyalgia patients.11 These people
all met ACR criteria for fibromyalgia, but this subgroup was not depressed,
they weren't anxious, they weren't very tender. They had enough tender
points to meet the ACR criteria, but they weren't very tender using more
sophisticated measures of pressure pain threshold. And they didn't have any
negative cognitive factors, in that they didn't catastrophize, and had a
moderate sense that they could control their pain. So in these people, they
didn't have psychologic factors that seemed to be driving their pain to be
worse, yet they had fibromyalgia. These people likely do fairly well with
the kinds of treatments that we now recommend giving people with fibromyalgia.

At the beginning of this talk, I usually ask people to remember a
fibromyalgia patient, and when I get to this point of the talk, I say that
that fibromyalgia patient that you remembered is in the second subgroup,
that we refer to as tertiary care fibromyalgia patients. You, as a
rheumatologist, are not well equipped to make this person better, because
what's going on in their spinal cord and brain with respect to their pain
processing is the least of their problems. In addition to being tender,
they're depressed, anxious, they catastrophize, they have no sense they can
control their pain. These are people that have very prominent psychological
factors above and beyond what might be contributing to their tenderness.
These are people that even the best multidisciplinary pain programs have
difficulty making better, and they certainly are not going to get better by
just giving them a drug that somehow modifies pain processing in the brain
or spinal cord. It is naive to think that you're going to make this kind of
person better by just giving them a drug, because superimposed on a central
nervous system problem with pain processing, these individuals have had
significant social, cognitive, behavioral, and psychologic consequences of
years or decades of untreated pain and other somatic symptoms.

The third subgroup that we identified in this study was very interesting.
This group was the most tender of the three, suggesting that there was
something quite wrong with how they processed pain. But despite this, these
people were not anxious, they weren't depressed, they weren't
catastrophizing. They actually had a moderate sense they could do something
about their pain. These are individuals in whom psychologic resiliency
seems to be buffering them against the neurobiological effects of
fibromyalgia. In spite of what's going on in their brain and their spinal
cord that is increasing their volume control setting and moving them to the
right side of the bell-shaped curve, somehow they're coping and they're
dealing with this condition much better than the other 2 groups. Several
groups are now exploring whether it is possible to instill this resiliency
into chronic pain patients. This is a relatively new thing in psychology;
psychologists until recently focused on psychopathology, on anxiety, on
depression, on the bad things that happen in psychology.

I've noted several times that the fundamental problem with this spectrum of
illness is in pain processing or sensory processing. One of the things that
you should be aware of is that in fibromyalgia, as well as in IBS and most
of the other conditions in this spectrum, it is not just painful stimuli to
which these people are more sensitive. They are more sensitive to auditory
loudness, bright lights, odors, and other sensory stimuli. In fact,
accounts for the overlap between multiple chemical sensitivity (which is a
misnomer) and fibromyalgia. Thus, it is appearing that this is not multiple
chemical sensitivity; it is really multiple sensory sensitivity. People are
just sensitive to a lot of different sensory stimuli.

Back to talking about the sensation of pain, there are a number of
different ways that people can theoretically move to the right end of this
bell-shaped curve, and have an increased volume control in pain processing.
Some of these mechanisms by which this occur involve peripheral nerves,
whereas others are central mechanisms, involving the brain or spinal cord.
One of the primary problems in fibromyalgia patients appears to be not that
there is too much input coming from the pressure nociceptors or the thermal
nociceptors, but rather that there is inadequate filtering of that
activity, perhaps because of decreased activity of descending
antinociceptive pathways.12,13 These pathways begin in the brain and
brainstem and descend into the dorsal horn of the spinal cord and are
normally responsible for inhibiting the upward transmission of pain. It
appears that these pathways are not working properly in individuals with
fibromyalgia. So a lot of nociceptive information that may be filtered out
in normal individuals may not be filtered out in fibromyalgia patients.

In addition to these studies that have used experimental pain testing to
elucidate some of the underlying mechanisms in fibromyalgia, one of the
other tools that you can use to look at pain processing in conditions like
fibromyalgia is functional imaging. Our group, led by Rick Gracely, has
performed many functional imaging studies in fibromyalgia. One of the big
advantages of using functional brain imaging is that, because of animal and
then later human studies that have been going on for the past 3 decades, we
now know the regions of the brain that are involved in pain processing.
Thus, we can give people painful stimuli under different conditions and
image the neuronal activation patterns to infer how pain processing is
different in fibromyalgia patients and controls. The areas of the brain
that are involved in the sensory dimension of pain, which is basically
where the pain located, and how much it hurts, are the primary and
secondary somatosensory cortex and thalamus.

There are other regions of the brain that are more involved in the
affective dimension of pain or the emotional valance of pain, or in how
they think about their pain, and these include regions such as the insula,
anterior cingulated, amygdale, and prefrontal cortex. In the first study
that used functional MRI to study pain processing in fibromyalgia, we gave
fibromyalgia patients a 2.5 kg stimulus to their thumb and asked them how
much it hurt on a 0 to 20 visual analog pain scale. We knew that they would
experience moderate pain at the same level of pressure that nonfibromyalgia
patients, healthy controls, experienced no pain. So we put the fibromyalgia
patients in the scanner and gave them the low amount of pressure, which in
them led to moderate pain, and then gave a group of healthy controls the
same amount of pressure (which they rated as barely painful), and then the
same amount of pain (by giving them twice as much pressure).

The hypothesis was very simple. If we saw similar neuronal activation
patterns in fibromyalgia patients getting the low pressure (which they felt
as moderately painful), and the controls getting the same amount of
pressure (which they barely felt), then that would indicate that
fibromyalgia is some type of a perceptual problem, because although the
fibromyalgia patients were having the same brain activation patterns, they
were perceiving it differently. In contrast, we saw that the fibromyalgia
patient's brain activation patterns were very similar with 2.5 kg of
pressure as the controls getting 4.5 kg of pressure. This was the first
objective evidence that there is augmented central pain processing in
people with fibromyalgia.14 We published another functional MRI study a
couple of years ago that showed that the level of depression that a
fibromyalgia patient has doesn't at all influence the level of pain in the
sensory areas of the brain.15 That suggests that depression and pain, when
they are present simultaneously, are really somewhat independent
constructs. We also have seen evidence of this in the clinical trials of
drugs that are mixed reuptake inhibitors or tricyclics in that whether
someone is depressed or not doesn't predict at all whether they're going to
respond to one of these drugs as an analgesic.16

In contrast, how people think about their pain might actually influence the
sensory processing of pain. In another fMRI study, we showed that
fibromyalgia patients that catastrophize actually have augmented neuronal
activation in the secondary somatosensory cortex.17 Dave Williams in our
group is just finishing a NIH-funded study that does functional imaging at
baseline in fibromyalgia patients who have an external locus of pain
control and then gives them several brief interventions to increase their
locus of control. We hypothesize that changing patient's cognitions (in
this case locus of pain control) will change the processing of pain in the
brain, even in brain regions thought to be involved in the sensory
processing of pain. Finally, we performed another fMRI study showing that
individuals with chronic idiopathic low back pain (low back pain with
normal lumbar MRIs) were indistinguishable from fibromyalgia patients with
respect to their pain sensitivity at their thumbnail and with respect to
their functional MRI findings.18 In aggregate, these and many other studies
in this spectrum of illness suggest that there is neurobiological evidence
of augmented central pain processing, and that in this setting, individuals
can experience pain even without appropriate peripheral nociceptive input.

TREATMENT
Now that I have outlined some of the underlying mechanisms in fibromyalgia
and related conditions, I'll finish by discussing treatment. Clinical-based
evidence advocates a multifaceted program emphasizing education, certain
medications, exercise, and cognitive therapy.19 However, the overwhelming
majority of fibromyalgia patients are not being appropriately treated at
present. Market surveys suggest that the no. 1 class of drugs currently
used to treat fibromyalgia in the United States is NSAIDs, whereas opioids
are no. 3 or 4, even though there is no evidence that either of these
classes of drugs works in fibromyalgia. Moreover, most fibromyalgia
patients are not being adequate education about their disease, nor are they
given access to exercise and cognitive behavioral therapy programs. So it
should not be surprising that these patients are frustrated and trying to
prove that they really have something wrong with them when they come in to
see us.

DIAGNOSIS AND EDUCATION
Once a physician rules out other potential disorders, an important and at
times controversial step in the management of fibromyalgia is making the
diagnosis. Despite some assumptions that being labeled with fibromyalgia
may adversely affect patients, a study by White et al. indicated that
patients had significant improvement in health satisfaction and symptoms
after being given this label.20 Nonetheless, in certain selected
individuals, i.e., adolescents, or individuals who may use the label as an
excuse for maladaptive illness behavior, I prefer not to use this label but
instead recommend the same type of treatment I would for a fibromyalgia
patient. Regardless of the label used or not used, although the diagnosis
of this condition should be coupled with patient education, an intervention
shown to be effective in many randomized controlled trials.

PHARMACOLOGICAL THERAPY
The most frequently studied pharmacological therapy for fibromyalgia is low
doses of tricyclic compounds. Most tricyclic antidepressants (TCAs)
increase the concentrations of serotonin and/or norepinephrine by directly
blocking their respective reuptake. Despite tolerability issues, the use of
TCAs (particularly amitriptyline and the biologically similar
cyclobenzaprine) to treat the symptoms of pain, poor sleep, and fatigue
associated with fibromyalgia is supported by several randomized, controlled
trials.21 The tolerability of TCAs can be improved by beginning at very low
doses (e.g., 5 to 10 mg of the above compounds), giving the dose a few
hours before bedtime, and very slowly escalating the dose.

Because of a better side-effect profile, newer antidepressants, i.e.,
selective serotonin reuptake inhibitors (SSRIs), are frequently used in
fibromyalgia. The SSRIs fluoxetine, citalopram, and paroxetine have each
been evaluated in randomized, placebo controlled trials in fibromyalgia,
and in general, the less selective drugs are effective at high doses. The
newer highly selective serotonin reuptake inhibitors, e.g., citalopram,
seem to be less efficacious than the older SSRIs in both animal and human
studies, perhaps because these latter compounds have noradrenergic activity
at higher doses.22

Because TCAs (and high doses of certain SSRIs such as fluoxetine and
sertraline) that have the most balanced reuptake inhibition are the most
effective analgesics, many in the pain field have concluded that dual
receptor inhibitors [serotonin-norepinephrine and norepinephrine-serotonin
reuptake inhibitors (SNRIs and NSRIs)] may be of more benefit than pure
serotonergic drugs. These drugs are pharmacologically similar to some TCAs
in their ability to inhibit the reuptake of both serotonin and
norepinephrine, but differ from TCAs in being generally devoid of
significant activity at other receptor systems. This selectivity results in
diminished side effects and enhanced tolerability. The first available
SNRI, venlafaxine, has data to support its use in the management of
neuropathic pain, and retrospective trial data demonstrate that this
compound is also effective in the prophylaxis of migraine and tension
headaches. Two studies in fibromyalgia have had conflicting results, with
the one using a higher dose showing efficacy.

Two new SNRIs, milnacipran and duloxetine, have undergone recent
multicenter trials.16,23 In the phase II trial evaluating milnacipran,
statistically significant positive differences were noted in overall
improvement, physical functioning, level of fatigue, and degree of reported
physical impairment. In the trial of duloxetine when compared with placebo,
participants treated with duloxetine had decreased self-reported pain and
stiffness and a reduced number of tender points. In the 2 above studies as
well as most studies that have used antidepressants as analgesics, the
benefits on pain and other symptoms were independent of the drug effect on
mood, thus suggesting that the analgesic and other positive effects of this
class of drugs in fibromyalgia is not simply because of their
antidepressant effects.

Antiepileptic drugs are widely used in the treatment of various chronic
pain conditions including postherpetic neuralgia and painful diabetic
neuropathy. Pregabalin is a ?-aminobutyric acid (GABA) analog and approved
for the treatment of neuropathic pain. A recent randomized, double-blinded,
placebo-controlled trial demonstrated efficacy of pregabalin against pain,
sleep disturbances, and fatigue in fibromyalgia.24 Similar results have
also been recently noted with gabapentin, a compound with similar
pharmacology to pregabalin.

Sedative-hypnotic compounds are widely used by fibromyalgia patients. A
handful of studies have been published on the use of certain
nonbenzodiazepine hypnotics in fibromyalgia, such as zopiclone and
zolpidem. These reports have suggested that these agents can improve the
sleep and, perhaps, fatigue of fibromyalgia patients, though they had no
significant effects upon pain. On the other hand, ?-hydroxybutyrate (also
known as sodium oxabate), a precursor of GABA with powerful sedative
properties, was recently shown to be useful in improving fatigue, pain, and
sleep architecture in patients with fibromyalgia.25 Note, however, that
this agent is a scheduled substance due to its abuse potential. Pramipexole
is a dopamine agonist indicated for Parkinson disease that has shown
utility in the treatment of periodic leg movement disorder, and a recent
study suggests that this compound may improve both pain and sleep in
fibromyalgia patients.26 Tizanidine is a centrally acting a2-adrenergic
agonist approved by the FDA for the treatment of muscle spasticity
associated with multiple sclerosis and stroke, and a recent trial reported
significant improvements in several parameters in fibromyalgia, including
sleep, pain, and measures of quality of life.27

There have been no adequate, randomized controlled clinical trials of
opiates in fibromyalgia, and many in the field (including myself) have not
found this class of compounds to be effective in anecdotal experience.
Tramadol is a compound that has some opioid activity (weak mu agonist
activity) combined with serotonin/norepinephrine reuptake inhibition. This
compound does appear to be somewhat efficacious in the management of
fibromyalgia, as both an isolated compound and as fixed-dose combination
with acetaminophen.28 Nonsteroidal anti-inflammatory drugs (NSAIDs) and
acetaminophen are used by a large number of fibromyalgia patients. Although
numerous studies have failed to confirm their effectiveness as analgesics
in fibromyalgia, there is limited evidence that patients may experience
enhanced analgesia when treated with combinations of NSAIDs and other
agents. This phenomenon may be a result of concurrent peripheral pain
conditions (i.e., osteoarthritis, tendonitis), which may be present in some
individuals, and/or that these comorbid peripheral pain generators might
lead to central sensitization and worsening of central pain.

NONPHARMACOLOGICAL THERAPIES
The 2 best-studied nonpharmacological therapies are cognitive behavioral
therapy and exercise. Both of these therapies have been shown to be
efficacious in the treatment of fibromyalgia, as well as a plethora of
other medical conditions.29 Both of these treatments can lead to sustained
(e.g., greater than 1 year) improvements and are very effective when an
individual complies with therapy.

Alternative therapies have been explored by patients managing their own
illness, as well as health care providers. As with other diseases, there
are few controlled trials to advocate their general use. Trigger-point
injections, chiropractic manipulation, acupuncture, and myofascial release
therapy are among the more commonly used modalities, which achieve varying
levels of success. Two recent randomized, sham-controlled trial of
acupuncture in fibromyalgia showed no difference between the efficacy in
active treatment and sham groups.30,31 There is some evidence that the use
of alternative therapies give patients a greater sense of control over
their illness. In instances where this sense of control is accompanied by
an improved clinical state, the decision to use these therapies is between
physicians and patients themselves.

SUMMARY
Chronic pain and fatigue syndromes such as fibromyalgia represent a part of
a clinical spectrum of overlapping disorders that afflict a significant
portion of the general proportion. Data suggest that there is a familial
tendency to develop these disorders, and that exposure to physical,
emotional, or environmental stressors' may trigger the initiation of
symptoms. Once the illness develops, the majority of the symptoms are
likely mediated by central nervous system mechanisms.

Management strategies are similar to other chronic illnesses, where
empathetic health care providers should develop a partnership with their
patients. At one end of the continuum, there are some individuals with
fibromyalgia that respond to a single medication or a graded, low-impact
exercise program. At the other end of the continuum is the tertiary care
patient with high levels of distress who has no sense of control of their
illness, little social support, and has looked toward disability and
compensation systems to try to solve their problem. For this individual,
and many in between, multimodal programs that integrate nonpharmacological
(especially exercise, CBT) and pharmacological therapies are required.

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© 2007 Lippincott Williams & Wilkins, Inc.

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