Background: Theories about the underlying etiology of chronic fatigue syndrome and which treatment is most effective are often debated. Three proposed treatments for chronic fatigue syndrome in addition to specialist medical care are graded exercise therapy, cognitive behavior therapy (CBT), and adaptive pacing therapy. Adaptive pacing therapy generally has been the treatment of choice, given its effectiveness. Patient advocacy organizations have been concerned about harm with graded exercise therapy and CBT; however, this recently has been challenged. White and colleagues conducted the Pacing, graded Activity, and Cognitive behaviour therapy: a randomised Evaluation (PACE) study to determine the effectiveness and safety of specialist medical care combined with CBT, graded exercise therapy, or adaptive pacing therapy compared with specialist medical care alone for the treatment of chronic fatigue syndrome.

The Study: A total of 641 patients with chronic fatigue syndrome diagnosed using the Oxford criteria were randomly allocated to four therapy groups: CBT and specialist medical care, graded exercise therapy and specialist medical care, adaptive pacing therapy and specialist medical care, and specialist medical care alone. Specialist medical care was provided by physicians with experience in chronic fatigue syndrome and consisted of disease explanation, advice, and symptomatic pharmacotherapy. Adaptive pacing therapy was provided by occupational therapists and focused on helping patients plan and pace activity to avoid fatigue. CBT was delivered by clinical psychologists and nurse therapists and was aimed at changing cognitive and behavioral factors responsible for patients' disability and symptoms. Graded exercise therapy was delivered by physiotherapists with the goal of reversing deconditioning and enabling patients to return to physical activity. Assessments were made at baseline, 12 weeks (midtherapy), 24 weeks (posttherapy), and 52 weeks after randomization. The primary outcomes were self-rated by the participants and measured by previously validated fatigue and physical function questionnaires. Secondary outcomes were collected from a seven-point clinical global impression scale, and a number of additional scales assessing overall disability. Patients also rated their satisfaction with treatment. Safety outcomes were measured by monitoring adverse events (serious and nonserious), serious adverse reactions to trial treatments, serious deterioration, and active withdrawal from treatment.

Results: Participants' expectations were high for adaptive pacing therapy and graded exercise therapy, but low for CBT and specialist medical care; however, therapy satisfaction was at least 82 percent for adaptive pacing therapy, graded exercise therapy, and CBT, and was 50 percent for specialist medical care. Therapeutic alliance scores and therapeutic adherence scores were high for all groups. Participants had less fatigue and better physical function after CBT and graded exercise therapy than after adaptive pacing therapy or specialist medical care alone. After 52 weeks, 59 percent of participants in the CBT group, and 61 percent in the graded exercise therapy group improved by at least two points on the fatigue scale and at least eight points on physical function, compared with 42 percent in the adaptive pacing therapy group, and 45 percent in the specialist medical care group. Statistically, patients improved more with CBT and graded exercise therapy compared with adaptive pacing therapy. Adaptive pacing therapy and specialist medical care did not differ. Additionally, 30 percent of the CBT group, and 28 percent of the graded exercise therapy group were within normal ranges of fatigue and physical function at 52 weeks, compared with only 16 percent in the adaptive pacing therapy group, and 15 percent in the specialist medical care group. Nonserious adverse events were common and equal among groups. Serious adverse events, serious adverse reactions, and serious deterioration were uncommon and did not differ between treatment groups. At 52 weeks, more participants rated their overall health as much better or very much better after CBT or graded exercise therapy than after adaptive pacing therapy or with specialist medical care. On average, participants had better secondary outcomes including improved work and social adjustment scores, less postexertional malaise, less sleep disturbance, less anxiety, and less depression after CBT or graded exercise therapy than after adaptive pacing therapy or with specialist medical care.

Conclusion: When added to specialist medical care, CBT and graded exercise therapy are more effective in reducing fatigue and improving physical function than adaptive pacing therapy or specialist medical care alone. Secondary outcomes show a similar pattern. No significant differences in safety were identified. Based on these findings, patients with chronic fatigue syndrome should be offered CBT or graded exercise therapy in addition to specialist medical care.