When added to SMC, CBT and GET had greater success in reducing fatigue and improving physical function than did APT or SMC alone. APT was no better than was SMC alone. Our findings were much the same for participants meeting the different diagnostic criteria for chronic fatigue syndrome and for myalgic encephalomyelitis, for those with depressive disorder, and after allowing for clustering effects. Other secondary outcomes showed a very similar pattern. There were no important differences in safety outcomes between treatment options.
Mean differences between groups on primary outcomes almost always exceeded predefined clinically useful differences for CBT and GET when compared with APT and SMC. In all comparisons of the proportions of participants who had either improved or were within normal ranges for these outcomes, CBT and GET did better than did APT or SMC alone. No more than 30% of participants were within normal ranges for both outcomes and only 41% rated themselves as much better or very much better in their overall health. We suggest that these findings show that either CBT or GET, when added to SMC, is an effective treatment for chronic fatigue syndrome, and that the size of this effect is moderate (panel 2
Panel 2. Research in context
We searched the PubMed and Cochrane Library databases up to Nov 6, 2010, without language restrictions for full papers reporting randomised controlled trials, systematic reviews, and meta-analyses with the search terms “chronic fatigue syndrome”, “myalgic encephalomyelitis”, “myalgic encephalopathy” and “cognitive behaviour therapy”, “exercise”, “pacing”. We excluded trials of adolescents, education, and group interventions. Our search identified the two most recent systematic reviews,4,5
and two additional trials34,35
that were not included in these reviews. The reviews and meta-analyses concluded that cognitive behaviour therapy and graded exercise therapy are moderately effective treatments for chronic fatigue syndrome, and that limitations of previous trials included small size, an absence of data for safety outcomes, and high dropout rates.4–7
The findings from these studies concur with the UK National Institute for Health and Clinical Excellence guidelines.2
In the pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation (PACE) trial, we affirm that cognitive behaviour therapy and graded exercise therapy are moderately effective outpatient treatments for chronic fatigue syndrome when added to specialist medical care, as compared with adaptive pacing therapy or specialist medical care alone. Findings from PACE also allow the following interpretations: adaptive pacing therapy added to specialist medical care is no more effective than specialist medical care alone; our findings apply to patients with differently defined chronic fatigue syndrome and myalgic encephalomyelitis whose main symptom is fatigue; and all four treatments tested are safe.
Our conclusions are supported by secondary outcomes, as both CBT and GET provided greater improvements than did APT and SMC for most outcomes. The objective walking test favoured GET over CBT, whereas CBT provided the largest reduction in depression. The comparatively greater reduction in postexertional malaise with both CBT and GET compared with the other two treatments is notable, since the risk of exacerbation of this symptom is commonly given as a reason to avoid treatments such as GET. The 47% prevalence of mood and anxiety disorders at baseline was much the same as that noted in previous trials in secondary care (38–56%).20,23,36
The equivalent use of antidepressants in the treatment groups implies that the differences in outcomes are unlikely to be attributable to these drugs.
There were no differences between groups in the proportions with serious deterioration or serious adverse reactions. The increased rate of serious adverse events with GET compared with SMC is unlikely to be important because serious adverse events were not thought by the independent scrutinisers to be related to treatment. Consequently, if these treatments are delivered as described, by similarly qualified and trained clinicians, patients need not be concerned about safety.37
The finding that APT when added to SMC was no more effective than SMC alone was contrary to our initial hypothesis. This finding might in part be caused by greater improvement after SMC than was expected. Suboptimum delivery of APT is an unlikely explanation because APT therapists were the most experienced; the therapeutic alliance and the adherence to manuals were rated highly in this group and participant satisfaction did not differ from that for other therapies. Since participants' confidence that APT would help them was much the same as for GET, and greater than that for CBT, they were unlikely to have been biased by negative expectations. The fundamental difference between APT and both CBT and GET is that APT encourages adaptation to the illness,13,17,18
whereas CBT and GET encourage gradual increases in activity with the aim of ameliorating the illness.2,4,7
Our results do not support pacing, in the form of APT, as a first-line therapy for chronic fatigue syndrome.
We plan to report relative cost-effectiveness of the treatments, their moderators and mediators, whether subgroups respond differently, and long-term follow-up in future publications. Our finding that studied treatments were only moderately effective also suggests research into more effective treatments is needed. The effectiveness of behavioural treatments does not imply that the condition is psychological in nature.
Our findings were strengthened by the small numbers of dropouts, high rates of acceptance of the treatments, use of manual-defined treatments provided by competent clinicians, high rates of participant satisfaction, adherence to manuals, and therapeutic alliance. The PACE findings can be generalised to patients who also meet alternative diagnostic criteria for chronic fatigue syndrome12
and myalgic encephalomyelitis13
but only if fatigue is their main symptom.11
Our trial had limitations. We excluded patients unable to attend hospital. Our results apply to patients referred to secondary care. SMC is not the same as usual medical care that might be provided by a family doctor; this study was not designed to compare SMC with usual medical care. Although more than 3000 patients attending clinics had to be screened to identify the 641 recruited, the commonest reason for exclusion at screening was not having chronic fatigue syndrome. We chose conventional criteria for defining clinically useful differences between treatments, although other thresholds could have been chosen.32
SMC was not as closely monitored or supervised as the other therapies, and participants receiving SMC alone had more sessions than did those in the therapy groups; this is unlikely to have affected comparisons between the groups. Masking of participants or clinicians to treatment allocation was not possible, and research assessors were also not masked. Primary outcomes were subjective and rated by participants. While this avoided investigator bias, it could be subject to other biases. Although participant-rated outcome measures could have been affected by expectations of treatment, which were highest for APT and GET, CBT was one of the two most effective treatments despite lower expectations.
Findings from the PACE trial suggest that individually delivered CBT and GET, when added to SMC, are more effective and as safe as APT added to SMC or SMC alone. Patients attending secondary care with chronic fatigue syndrome should be offered individual CBT or GET, alongside SMC.