Lucy V Clark

Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial

BACKGROUNDnTrial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments.nnnMETHODSnIn our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094.nnnFINDINGSnWe recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p = 0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p = 0·0003), but did not differ for APT (0·7 [-0·9 to 2·3] points lower; p = 0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p = 0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p = 0·0005), but did not differ for APT (3·4 [-1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p = 0·0027; GET p = 0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group.nnnINTERPRETATIONnCBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition.nnnFUNDINGnUK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.

The role of deconditioning and therapeutic exercise in chronic fatigue syndrome (CFS)

Background: Patients with chronic fatigue syndrome (CFS) complain of tiredness or exhaustion, which is made worse by physical exertion. This results in their avoidance of exercise, which may lead to physical deconditioning. We do not know whether this deconditioning maintains the illness or is a consequence. Graded exercise therapy aims to reverse this cycle of inactivity and deconditioning, and to subsequently reduce the fatigue and disability associated with CFS. Aims: To review the literature relating to the role of deconditioning in perpetuating CFS and the literature relating to the role of graded exercise therapy as a treatment of CFS. Method: Non-systematic review of published papers concerning deconditioning and therapeutic exercise in patients with CFS. Findings: Patients with CFS are at least as deconditioned as sedentary but healthy controls. Supervised graded exercise therapy reduces fatigue and disability in ambulant patients with CFS; efficacy may be independent of reversing deconditioning. Conclusions: Graded exercise has an important role to play in the treatment of patients with CFS. Further work is necessary to elucidate the risks, benefits, and mechanisms of such treatment, especially in children and the severely disabled. Patient education is necessary to inform patients of the positive benefit/risk ratio in order to improve acceptance and adherence.

Service use and costs for people with headache: a UK primary care study

This paper aims to estimate the service and social costs of headache presenting in primary care and to identify predictors of headache costs. Patients were recruited from GP practices in England and service use and lost employment recorded. Predictors of cost were identified using regression models. Service and social costs were available on 288 and 282 patients, respectively. Average service costs over 3xa0months were £117 whilst total costs (including lost production) were £582. Patients referred to neurologists had service costs that were £82 higher than those not referred (90% CI £36–£128). Costs including lost employment were higher by £150, but this was not significant (90% CI -£139–£439). The annual mean service and social costs, weighted to represent population rates of referral, were £468 and £2328, respectively. Higher costs were significantly related to pain. Age was linked to higher service costs and lower social costs. The figures extrapolated to the whole of the UK suggest £956 million due to service use and £4.8 billion including lost employment. These are likely to be underestimates because many people experiencing headaches do not consult their GP.

Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial

Summary Background Graded exercise therapy is an effective and safe treatment for chronic fatigue syndrome, but it is therapist intensive and availability is limited. We aimed to test the efficacy and safety of graded exercise delivered as guided self-help. Methods In this pragmatic randomised controlled trial, we recruited adult patients (18 years and older) who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome from two secondary-care clinics in the UK. Patients were randomly assigned to receive specialist medical care (SMC) alone (control group) or SMC with additional guided graded exercise self-help (GES). Block randomisation (randomly varying block sizes) was done at the level of the individual with a computer-generated sequence and was stratified by centre, depression score, and severity of physical disability. Patients and physiotherapists were necessarily unmasked from intervention assignment; the statistician was masked from intervention assignment. SMC was delivered by specialist doctors but was not standardised; GES consisted of a self-help booklet describing a six-step graded exercise programme that would take roughly 12 weeks to complete, and up to four guidance sessions with a physiotherapist over 8 weeks (maximum 90 min in total). Primary outcomes were fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale); both were self-rated by patients at 12 weeks after randomisation and analysed in all randomised patients with outcome data at follow-up (ie, by modified intention to treat). We recorded adverse events, including serious adverse reactions to trial interventions. We used multiple linear regression analysis to compare SMC with GES, adjusting for baseline and stratification factors. This trial is registered at ISRCTN, number ISRCTN22975026. Findings Between May 15, 2012, and Dec 24, 2014, we recruited 211 eligible patients, of whom 107 were assigned to the GES group and 104 to the control group. At 12 weeks, compared with the control group, mean fatigue score was 19·1 (SD 7·6) in the GES group and 22·9 (6·9) in the control group (adjusted difference −4·2 points, 95% CI −6·1 to −2·3, p<0·0001; effect size 0·53) and mean physical function score was 55·7 (23·3) in the GES group and 50·8 (25·3) in the control group (adjusted difference 6·3 points, 1·8 to 10·8, p=0·006; 0·20). No serious adverse reactions were recorded and other safety measures did not differ between the groups, after allowing for missing data. Interpretation GES is a safe intervention that might reduce fatigue and, to a lesser extent, physical disability for patients with chronic fatigue syndrome. These findings need confirmation and extension to other health-care settings. Funding UK National Institute for Health Research Research for Patient Benefit Programme and the Sue Estermann Fund.

Response to the editorial by Dr Geraghty

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty’s views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control study

Chronic fatigue syndrome (CFS) is characterized by fatigue after exertion. A systematic review suggested that transforming growth factor (TGF)‐β concentrations are often elevated in cases of CFS when compared to healthy controls. This study attempted to replicate this finding and investigate whether post‐exertional symptoms were associated with altered cytokine protein concentrations and their RNA in CFS patients. Twenty‐four patients fulfilling Centers for Disease Control criteria for CFS, but with no comorbid psychiatric disorders, were recruited from two CFS clinics in London, UK. Twenty‐one healthy, sedentary controls were matched by gender, age and other variables. Circulating proteins and RNA were measured for TGF‐β, tumour necrosis factor (TNF), interleukin (IL)‐8, IL‐6 and IL‐1β. We measured six further cytokine protein concentrations (IL‐2, IL‐4, IL‐5, IL‐10, IL‐12p70, and interferon (IFN)‐γ). Measures were taken at rest, and before and after both commuting and aerobic exercise. CFS cases had higher TGF‐β protein levels compared to controls at rest (median (quartiles)u2009=u200943·9 (19·2, 61·8) versus 18·9 (16·1, 30·0) ng/ml) (Pu2009=u20090·003), and consistently so over a 9‐day period. However, this was a spurious finding due to variation between different assay batches. There were no differences between groups in changes to TGF‐β protein concentrations after either commuting or exercise. All other cytokine protein and RNA levels were similar between cases and controls. Post‐exertional symptoms and perceived effort were not associated with any increased cytokines. We were unable to replicate previously found elevations in circulating cytokine concentrations, suggesting that elevated circulating cytokines are not important in the pathophysiology of CFS.

Graded Exercise Therapy Guided Self-Help Trial for Patients with Chronic Fatigue Syndrome (GETSET): Protocol for a Randomized Controlled Trial and Interview Study

Background Chronic fatigue syndrome, also known as myalgic encephalomyelitis (CFS/ME), is characterized by chronic disabling fatigue and other symptoms, which are not explained by an alternative diagnosis. Previous trials have suggested that graded exercise therapy (GET) is an effective and safe treatment. GET itself is therapist-intensive with limited availability. Objective While guided self-help based on cognitive behavior therapy appears helpful to patients, Guided graded Exercise Self-help (GES) is yet to be tested. Methods This pragmatic randomized controlled trial is set within 2 specialist CFS/ME services in the South of England. Adults attending secondary care clinics with National Institute for Health and Clinical Excellence (NICE)-defined CFS/ME (N=218) will be randomly allocated to specialist medical care (SMC) or SMC plus GES while on a waiting list for therapist-delivered rehabilitation. GES will consist of a structured booklet describing a 6-step graded exercise program, supported by up to 4 face-to-face/telephone/Skype™ consultations with a GES-trained physiotherapist (no more than 90 minutes in total) over 8 weeks. The primary outcomes at 12-weeks after randomization will be physical function (SF-36 physical functioning subscale) and fatigue (Chalder Fatigue Questionnaire). Secondary outcomes will include healthcare costs, adverse outcomes, and self-rated global impression change scores. We will follow up all participants until 1 year after randomization. We will also undertake qualitative interviews of a sample of participants who received GES, looking at perceptions and experiences of those who improved and worsened. Results The project was funded in 2011 and enrolment was completed in December 2014, with follow-up completed in March 2016. Data analysis is currently underway and the first results are expected to be submitted soon. Conclusions This study will indicate whether adding GES to SMC will benefit patients who often spend many months waiting for rehabilitative therapy with little or no improvement being made during that time. The study will indicate whether this type of guided self-management is cost-effective and safe. If this trial shows GES to be acceptable, safe, and comparatively effective, the GES booklet could be made available on the Internet as a practitioner and therapist resource for clinics to recommend, with the caveat that patients also be supported with guidance from a trained physiotherapist. The pragmatic approach in this trial means that GES findings will be generalizable to usual National Health Service (NHS) practice. Trial Registration International Standard Randomized Controlled Trial Number (ISRTCTN): 22975026; http://www.isrctn.com/ISRCTN22975026 (Archived by WebCite at http://www.webcitation.org/6gBK00CUX)

Predictors of outcome in patients consulting their general practitioners for headache: A prospective study

Headache is the most common neurological symptom presenting to general practitioners (GPs). Identifying factors predicting outcome in patients consulting their GPs for headache may help GPs with prognosis and choose management strategies which would improve patient care. We followed up a cohort of patients receiving standard medical care, recruited from 18 general practices in the South Thames region of England, approximately 9 months after their initial participation in the study. Of the baseline sample (Nu2009=u2009255), 134 provided both full baseline and follow-up data on measures of interest. We determined associations between patients’ follow-up scores on the Headache Impact Test-6 and baseline characteristics (including headache impact and frequency scores, mood, attributions about psychological/medical causes of their headaches, satisfaction with GP care and illness perceptions). Greater impact and stronger beliefs about the negative consequences of headaches at baseline were the strongest predictors of poor outcome at follow-up.