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ORIGINAL ARTICLES |
From the Department of Psychological Medicine, University of Auckland, Auckland, New Zealand (K.v.K.); School of Psychology, University of Southampton, Highfield Southampton, UK (R.M.-M.); Auckland City Hospital, Neurology Department, Auckland, New Zealand (E.W.); Academic Department of Psychological Medicine, Guy’s, King’s and St Thomas’ School of Medicine, Weston Education Centre, Cutcombe Road, London (T.C.); Department of Psychological Medicine, University of Auckland, Auckland, New Zealand (M.H.J.); and Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand (E.R.).
Address correspondence and reprint requests to Dr. Rona Moss-Morris, School of Psychology, University of Southampton, Highfield Southampton, SO17 1 BJ, UK. E-mail: R.E.Moss-Morris{at}soton.ac.uk
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ABSTRACT |
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Methods: A randomized controlled design was used where 72 patients with MS fatigue were randomly assigned to eight weekly sessions of CBT or relaxation training (RT). RT was designed to control for therapist time and attention. Participants were assessed before and after treatment, and at 3 and 6 months posttreatment. The primary outcome was the Fatigue Scale. Secondary outcomes included measures of stress, mood, and fatigue-related impairment.
Results: Analysis was by intention-to-treat. A group by time interaction showed that the CBT group reported significantly greater reductions in fatigue across the 8 months compared with the RT group (p < .02). Calculated effect sizes for fatigue from baseline to the end of treatment were 3.03 [95% confidence interval, 2.22–3.68] for the CBT group and 1.83 [95% confidence interval, 1.26–2.34] for the RT group. Results also indicted that both groups showed clinically significant decreases in fatigue defined as fatigue levels equivalent or less than those reported by a nonfatigued healthy comparison group. There were no significant interactions between group and any of the secondary outcome variables, with both groups showing improvements over time on all measures.
Interpretation: Both CBT and RT appear to be clinically effective treatments for fatigue in MS patients, although the effects for CBT are greater than those for RT. Even 6 months after treatment, both treatment groups reported levels of fatigue equivalent to those of the healthy comparison group.
Key Words: Multiple sclerosis • fatigue • cognitive behavior therapy • randomized controlled trial
Abbreviations: MS = multiple sclerosis; CBT = cognitive behavior therapy; RT = relaxation training; RCT = randomized controlled trial; EDSS = expanded disability status scale; HADS = the hospital anxiety and depression scale.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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A number of clinical trials have tested a variety of treatments for MS fatigue. There is some evidence that pharmacotherapy may be useful in treating fatigue in some MS patients (8–15). However, these effects are at best modest, and two studies found no significant difference in outcome between the medication and placebo groups (10,16). Nonpharmacological treatment trials have found some evidence for benefits of aerobic exercise, although results are limited due to small numbers and lack of follow-up evaluations (17,18).
A common weakness of the treatment studies to date is that they are not founded on a clear conceptualization of MS fatigue. We have recently developed a cognitive behavior model to explain MS fatigue that integrates the findings across biological and psychosocial research (19). This model proposes that primary disease factors trigger the initial symptom of fatigue in MS, and the fatigue is perpetuated or worsened depending on how people react to the fatigue cognitively, emotionally, behaviorally, and physiologically.
The purpose of this study was to investigate the efficacy of an intervention based on this cognitive behavior model to treat fatigue in MS. To our knowledge, there are no existing studies of cognitive behavior therapy (CBT) for fatigue in MS. However, three randomized controlled trial (RCTs) of CBT for chronic fatigue syndrome have reported significant improvements in fatigue (20–22), and CBT has been found to be effective in reducing depression in MS patients (23).
In this RCT we compared our manualized CBT package to relaxation training (RT), which was designed to control for nonspecific treatment factors including therapist attention and support, expectations, and homework practice. We hypothesized that patients assigned to CBT would show significantly greater improvements in fatigue (our primary outcome) at the end of treatment compared with patients assigned to RT. To determine whether gains were clinically significant, we collected fatigue data for a matched healthy comparison group at the beginning of the trial. A clinically significant change was defined as a mean fatigue level equivalent to the fatigue levels in the healthy comparison group. We also hypothesized that the CBT group would demonstrate significantly greater improvements in fatigue-related impairment and mood (anxiety, depression, and stress) at the end of treatment. Finally, we were interested in whether gains were maintained over a 6-month follow-up period.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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Patients who consented to be contacted by the research team were then screened on the telephone to assess eligibility. Inclusion criteria included a) a diagnosis of MS based on the McDonald criteria, which incorporate clinical features with magnetic resonance scanning and other investigations; b) an Expanded Disability Status Scale (EDSS) score of 6.0 or less, which identifies patients who are still ambulatory with or without a stick for at least 100 m (24); c) a fatigue score of 4 or greater. A cut-off of 4 on the Fatigue Scale has been identified as a case level of fatigue (25); and d) willingness to abstain from any new psychological or pharmacological treatment during the duration of the study.
Patients established on beta-interferon and/or anti-depressant treatments for longer than 3 months were included but patients with any serious psychological disorders for which study participation would be inappropriate (including psychotic disorders or active substance abuse), or those with any chronic illness that may be contributing to fatigue were excluded. Patients who met these criteria via self-report and who consented to enter the study were then assessed by a neurologist (E.W.) to confirm their diagnosis, type of MS, EDSS score, and current medication status.
Randomization
After patient inclusion was confirmed, patients were allocated sequentially by block wise randomization (block size of 10) using a computerized randomization programmed to one of two conditions. The allocation was concealed in a series of numbered sealed envelopes, which were handed onto an independent administrator. Each new subject entering the trial was allocated a number before the pretreatment assessments, and this number corresponded with a numbered envelope assigned by the independent administrator, which was opened by the therapist (K.v.K.) immediately before the first therapy session.
Treatment Procedure
The treatment phase began in July 2004 and ended in September 2005. Participants in both groups were seen individually for eight weekly sessions of up to 50 minutes each by the same therapist. Three of the sessions were face-to-face, where the patient came into the hospital to meet with the therapist. The other five sessions were completed by telephone to increase the likelihood of attendance and reduce the stress of travel for participants. Telephone delivered CBT for MS patients has been shown to be successful (23).
Participants in both groups were given a manual that was designed like a workbook, and served as a visual aid during the telephone sessions. The manual included a chapter of information for each week as well as structured homework sheets. All sessions followed a similar format, which included an agenda, a review and questions from the previous week, a review of homework tasks, followed by an introduction of the new "topic," setting new practice tasks, and a brief summary and questions at the end.
Cognitive Behavior Therapy
The CBT manual was written specifically for this trial1 and was based on a cognitive behavior model of fatigue (19). The sessions were collaborative in style, and the therapist used Socratic questioning wherever possible. The main aim was to challenge any behavioral, cognitive, emotional and external factors that may be contributing to MS fatigue. Sessions were individually tailored and the manual was designed so that patients could focus on aspects which they felt were relevant to them and ignore aspects which were less relevant. A summary of the broad content of each session is provided in Table 1.
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The first two sessions introduced participants to the CBT model of MS fatigue, and provided a detailed treatment rationale. An individualized CBT model for fatigue was developed collaboratively and developed throughout the therapy. Goals were set and monitored throughout the program according to the specific issues identified in the individual fatigue model. Sessions 3 and 4 concentrated on behavioral strategies with cognitive strategies introduced in session 5 (while continuing with the graded activity, rest and sleep goals). In the final session, strategies for dealing with setbacks were discussed and patients identified how they planned to continue the progress made in terms of improving their fatigue.
Both the CBT and RT manuals were based in part on the work by Deale and colleagues, who developed a CBT and relaxation manual for their RCT of CBT for chronic fatigue syndrome (20). However, a number of the CBT chapters were developed specifically for MS.
Relaxation Training
To control for therapist contact and support, expectations, homework tasks, etc, RT participants were taught a series of relaxation techniques during the eight sessions, including diaphragmatic breathing, progressive muscle relaxation, visualization, cue-controlled relaxation, and rapid relaxation. In order to engage patients, the rationale for teaching relaxation was built on the idea that stress may exacerbate and/or contribute to fatigue in MS through muscle tension. The aim was therefore to learn how to consciously relax and reduce muscle tension, which can be a result of stress.
The RT sessions followed the same session structure as the CBT sessions. No advice was given about scheduling activity, reducing rest, managing sleep problems, or cognitive strategies. The treatment manual was supplemented with a CD, which contained an audio version of each of the relaxation techniques taught. This made it easy for participants to do relaxation during telephone sessions, and allowed for consistency of technique and practice across all participants. The first session involved engagement and explanation of the rationale followed by the demonstration of diaphragmatic breathing. The remaining sessions followed a similar format of reviewing participants’ practice of the relaxation technique, introducing a new relaxation technique, live practice during the face-to-face session or during the phone session using the supplied CD, followed by a brief discussion of participants’ experience and/or questions about the new technique.
Treatment Fidelity and Validity of the Control Treatment
One CBT trained clinical psychologist (K.v.K.) provided the therapy for all the participants over a period of 14 months. To ensure adherence to the model and approach, the therapist received clinical supervision once every 2 weeks during the intervention phase of the trial.
To assess treatment fidelity, all face-to-face therapy sessions were audio taped and a random sample of 60 audiotapes (approximately 30% of total sessions taped) were analyzed by two independent raters using an adapted version of the Primary Care Therapy Rating Scale (26). Individual items reflecting key aspects of each treatment were scored from 1 (not at all) to 4 (extensively) rather than 1 to 7 as in the original scale. High ratings indicated good adherence to the specific components of the protocols.
Before treatment allocation, participants were asked to rate their initial treatment preference. To assess the face validity of the relaxation condition, participants rated at baseline how logical they found their treatment model and how confident they were that treatment would help their fatigue. At the end of treatment, participants rated how useful they found the intervention.
Assessments and Outcome Measures
Self-rated outcome measures were completed at baseline (Time 1), 2 months later at the end of treatment (Time 2), and at 3 (Time 3) and 6 months posttreatment (Time 4). Baseline assessments included the EDDS (24), which was completed by the neurologist (E.W.) and was repeated at Time 4 to determine any substantial change in MS-related disability during the trial.
The primary outcome measure was the Fatigue Scale (25), which is an 11-item questionnaire measuring the severity of physical and mental fatigue. The Fatigue Scale was used because it provides a relatively pure measure of fatigue severity, as opposed to other measures that rate fatigue severity indirectly on its impact on aspects of life (3). The scale can be scored using a bimodal system, where the first two items are scored 0 and the second two are scored as 1. This system was used to obtain a fatigue score during the initial screen on the telephone, to assess whether the person met the inclusion criterion of a case level of fatigue (cut-off of 4). In accordance with other CBT treatment trials (20), the "Likert" scoring method was used for scoring the primary outcome. Here items are scored 0 to 3 and summed to produce a total score with high scores representing high fatigue. The internal reliability of the fatigue scale as measured by Cronbach’s alpha at each time point in this trial ranged from 0.79 to 0.92.
To define clinically significant improvement in fatigue, a normative approach was used (27), which assessed whether patients’ fatigue levels after treatment were equivalent to fatigue levels in healthy people. In order to do this, we collected Fatigue Scale data from a matched healthy comparison group recruited during baseline assessments. The 72 MS participants were matched to 72 healthy participants by age, gender, and ethnicity. Healthy participants were screened via interview to exclude the presence of an existing chronic mental or physical illness. The details of these data are presented in the Results section.
Secondary outcome measures included the Work and Social Adjustment Scale (28), which assessed fatigue-related impairment in relation to a number of areas of the person’s life. The Hospital Anxiety and Depression Scale (29), a commonly used self-report instrument for detecting states of depression and anxiety in patients with medical illnesses, was used to assess if improvements in mood occurred after the intervention. Finally, the Perceived Stress Scale (30) was included to assess whether the degree to which patients appraised situations in their lives as stressful changed after the intervention.
Other measures used in the study were the Epworth Sleepiness Scale (31), the Sleep Problems Questionnaire (32), and the Brief Illness Perceptions Questionnaire (33). These measures were included to investigate predictors and mechanisms of change, and will be reported elsewhere.
Power Calculation
The sample size calculation for this study was based on a study which compared the effectiveness of CBT with relaxation therapy in chronic fatigue patients (20). The effect size was calculated on the composite fatigue score obtained from the two groups at 6 months follow-up. The effect size for the differences between the groups at this time point was 0.77. With 80% power and 0.05 significance, we needed 27 patients in each group to complete the trial to obtain a significant effect. We anticipated a maximum attrition of 20% at 6-months follow-up giving a total n of 33 patients per group.
Statistical Analysis
Statistical analyses were performed using the SPSS for Windows statistical software package (version 13; SPSS, Inc, Chicago, IL). All treatment effect analyses were by intention-to-treat. For participants that dropped-out, scores from the previous time point were carried forward. A series of 2 (group) x 4 (time) ANCOVAs with a repeated measure on the second factor were used to determine whether there was a significant group by time interaction on the primary and secondary outcome measures. EDSS and MS type were entered as covariates. Significant interaction effects were investigated using a priori repeated contrasts, which compared each category (except the first) to the previous category. This contrast allowed us to assess a) if was there a significant treatment effect at the end of the intervention period (contrasting the end of treatment scores at 2 months with the baseline scores), and b) if gains were maintained during the follow-up period (contrasting the 3-month follow-up data to end of treatment data, and 6-month follow-up to 3-month follow-up). Independent samples t tests were used to compare the healthy comparison group scores with the scores obtained from the two MS treatment groups at each measurement time point.
Sensitivity analyses were conducted to examine whether protocol violations, and/or changes in factors unique to the MS participants in this study, had an effect on the primary outcome measure of fatigue. These included withdrawal from the study, change in medication, presence of relapse, and change in level of disability (EDSS score).
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RESULTS |
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Thirty-five participants were randomly assigned to the CBT group, and 37 to the RT group. For the CBT group, 35 subjects (100%) completed the eight-session intervention, posttreatment and 3-month follow-up, and 34 (97%) the 6-month follow-up. In the RT group, 35 participants (95%) completed the eight-session intervention and all three follow-ups. Two people dropped out during treatment. In total, three people (4%) dropped out during the duration of the study, and reasons given were finding the RT intervention unhelpful (n = 1) and lack of time (n = 2). Data from all 72 participants were analyzed.
The demographic and illness characteristics of participants randomized to the CBT and RT groups are shown in Table 2 together with the relevant demographics of the matched healthy comparison group. The majority of the participants were female (75%) and European (94%), and the mean age across the groups was mid forties. The table shows that the three groups were well matched on these characteristics. The majority of the MS patients had relapsing remitting MS. However, there were more patients with primary progressive MS in the RT group and this group also appeared to have slightly higher EDSS scores than the CBT group. Therefore, MS type and EDSS score were controlled for in all outcome analyses. A similar number of people in both groups were taking medication at the start of the trial, with anti-depressants the most common.
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Treatment Fidelity and Validity of the Control Treatment
Results on the adapted version of the Primary Therapy Rating Scale showed that on 6 of the 7 CBT items, scores fell between 3 and 4 reflecting good adherence to the protocol on behalf of the therapist, with the remaining item scoring 2.6 which was still within an acceptable range. Ratings on the RT items reflected a similar pattern. Inter-rater reliability calculated using Cohen’s weighted kappa showed fair to good agreement on all items, with values ranging from 0.37 to 0.87 and most of the items above 0.6.
In terms of face validity of the relaxation versus CBT condition, at baseline there was no significant difference in how logical the groups found their treatment model (CBT M (SD) = 0.71 (1.17); RT M (SD)=1.10 (1.26); t = –1.36 (p = .18)). Similarly, no significant difference was obtained between groups in terms of how confident participants were that treatment would help their fatigue, with 0 = extremely confident and 8 = not confident at all (CBT M (SD) = 1.62 (1.23); RT M (SD) = 1.97 (1.73); t = –0.97 (p = .34)).
Patients’ ratings of their initial treatment preference at Time 1 were also similar across groups. In the CBT group, 16 people (45.7%) preferred to receive CBT, 17 (48.6%) preferred relaxation, and two (5.7%) had no preference. In the RT group, 20 people (54%) preferred CBT while 17 (45.9%) preferred relaxation. A two-way contingency table analysis showed that group and preference were not significantly related, Pearson 
2 (2, N = 72) = 2.39, p = .30.
At the conclusion of treatment, there was no significant difference with regards to how the two groups rated the usefulness of the program, with 0 = very useful and 4 no use at all (CBT M (SD) = 0.76 (0.95); RT M (SD) = 0.97 (0.85); t = –0.94 (p = .34)).
Primary Outcome
The pattern of change in fatigue scores in the CBT and RT groups across the assessment periods is shown in Figure 2, and the means and standard deviations are presented in Table 3. There was a significant Group by Time interaction (F(2.79, 189.82) = 3.60, p = .02), indicating that the CBT group improved significantly more over time on fatigue than the RT group.
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Calculated effect sizes for fatigue from baseline to the end of treatment were 3.03 [95% confidence interval (CI), 2.22–3.68] for the CBT group and 1.83 [95% CI, 1.26–2.34] for the RT group. The between group effect size was 0.76, which according to Cohen is a large effect size (34). Effect sizes from baseline to 6 months follow-up were 1.99 [95% CI, 1.36–2.49] for CBT and 1.64 [95% CI, 1.09–2.14] for the RT group, with a moderate between group effect size of 0.36 (34).
Tests of a priori within-subjects contrasts revealed that there was a significant difference between the CBT and RT groups at the end of treatment (F (1, 68) = 10.91, p > .001). No significant time or interaction effects were obtained on the other contrasts (the follow-up period), suggesting that while gains were maintained over time, patients did not continue to improve over time.
A number of sensitivity analyses were conducted to examine whether major protocol violations, or changes in factors unique to the MS participants in this study, had an impact on the Fatigue Scale results. These included withdrawal from the study (three people), change in medication (five people), presence of relapse (seven people), and change in level of disability (EDSS score) (five people). The sensitivity analyses showed a pattern of results similar to that from the main analyses. This suggests that these factors are unlikely to have biased the results.
To assess clinically significant improvement, fatigue scores for the MS samples were compared with baseline data from the matched healthy comparison group at each time point. These comparisons are represented graphically in Figure 2. The mean Fatigue Scale score for the healthy comparison group was 12.49 (SD = 2.86). Figure 2 shows that there were large significant differences between fatigue reported by the healthy comparison group at the start of treatment and the fatigue in the CBT (t (107) = 11.99; p < .001) and fatigue in the RT group (t (109) = 11.21; p < .001). Interestingly, at the end of treatment, the CBT group reported significantly lower levels of fatigue compared with the healthy comparison group normative score (t (107) = –6.67; p < .001). This trend for lower fatigue than healthy participants was maintained at 3 (t (107) = –4.48; p < .001) and 6 months follow-up (t (107) = –2.51; p < .01).
Fatigue levels for the RT group at the end of treatment were equivalent to those of the matched healthy comparison group (t (109) = –1.32; p = 0.19). At 3 months follow-up, their fatigue was significantly less than the healthy participants fatigue levels (t (109) = –2.08; p < .05), while the two groups had similar fatigue severity scores at the last follow-up point (t (109) = –0.14; p = .89).
Secondary Outcomes
The means and standard deviations for the secondary outcomes are presented in Table 3. No significant group by time interaction effects were found for any of the secondary outcome measures suggesting that there were no overall group differences on these measures including: fatigue-related impairment (F (3, 204) = 1.22, p = .30), depression (F (3, 204) = 1.96, p = .12), anxiety (F (2.43, 165.19) = 2.18, p = .11), and perceived stress (F (3, 204) = 1.92, p = .13).
However, tests of the a priori within-subjects contrasts revealed that a number of significant contrasts for the interaction effect were observed between baseline and end of treatment. This was the case for depression (F (1, 68) = 3.97, p = .05), anxiety (F (1, 68) = 6.13, p = .02), and perceived stress (F (1, 68) = 4.68, p = .03), suggesting that the CBT group showed significantly greater improvements on these measures at the end of treatment than did the RT group, but not at follow-up.
A significant time effect was obtained for all of the secondary outcomes: fatigue-related impairment (F (3, 204) = 4.05, p = .01), depression (F (3, 204) = 3.80, p = .01), anxiety (F (2.43, 165.19) = 4.76, p = .01), and perceived stress (F (3, 204) = 4.91, p = .00) with both groups showing a significant decrease in these measures (Table 3).
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DISCUSSION |
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Our data also suggested that the improvements in fatigue were clinically significant. Fatigue scores for the CBT group improved after treatment to a level lower than fatigue scores reported by a matched healthy comparison group, and this pattern was maintained at both follow-up points. The RT group improved to a level similar to that of the matched healthy comparison group, and this pattern was maintained at the last follow-up point. These results support the findings that CBT was more effective in improving MS fatigue than RT and also highlight that the RT group improved their fatigue to a level comparable to a healthy group.
Both the CBT and RT groups reported significant gains on all the secondary outcomes, including depression, anxiety, stress, and fatigue-related impairment. The gains for depression, anxiety, and stress were significantly greater for the CBT group than the RT group at the end of treatment, but not at 6 months follow-up. These results suggest that improving fatigue in MS has positive benefits for a number of aspects of life.
The beneficial effects of the eight face-to-face and telephone sessions of CBT were detectable up to 6 months after treatment ended, both in terms of fatigue and secondary outcome measures. However, the trend in scores for fatigue were such that the greatest improvement occurred between baseline and end of treatment, with the CBT group losing a little of the gain at 6 months follow-up, while the RT group tended to stay the same after the initial improvement. One explanation for this could be the significant amount of material and concepts covered during the 8 weeks of CBT. Participants in the CBT group would have had to practice newly acquired skills, some of which were quite complex, on their own after treatment was completed. In comparison, the RT group practiced relaxation techniques, which may have been easier to continue with compared with CBT skills.
Another explanation for the trend over time in the CBT group could be that the number of sessions offered was too small. It is possible that the CBT group could benefit from a slightly longer intervention, perhaps 10 sessions. This concept is supported by the fact that an RCT of CBT versus relaxation for chronic fatigue offered 13 sessions spread over 4 to 6 months (20). Similarly, booster sessions could have been another alternative to reinforce the CBT skills learnt during the intervention. So although the results for the CBT group show a clinically useful effect, research is required to determine whether patients would benefit from a larger number of CBT sessions and/or "booster" sessions to maintain their initial improvement. A longer duration would allow for greater skill acquisition, relapse prevention, and an opportunity for practicing self-directed treatment while still having therapist contact. On the other hand, the CBT group were still significantly less fatigued than the matched healthy comparison group so it may be unrealistic to improve fatigue levels further.
The fact that the RT group improved significantly on fatigue and the secondary outcomes was contradictory to the original hypotheses. It is possible that MS fatigue improved across both the CBT and RT conditions because of the nonspecific treatment factors including support, therapist time and attention, and expectations common to both conditions. This is consistent with a study that compared telephone administered CBT with supportive emotion focused therapy, and which reported that treatment differences obtained during treatment were not maintained at follow-up (23). The improvement in the RT group could also be explained by the fact that although relaxation was selected to control for nonspecific treatment factors, it may have included components which are traditionally associated with CBT such as collaboration, active participation, agenda setting, session format and use of manuals and homework.
Fidelity checks of the treatments confirmed that the therapist stuck to the protocols for each of the therapies. Our validity checks of the control condition also suggest that participants in both groups were confident in the effectiveness of their allocated treatment, thought the rationale for treatment was logical and rated the interventions as highly useful. This suggests that both CBT and RT are seen to be acceptable treatment options for patients with MS fatigue.
Potential Limitations of Study
The use of a single therapist for both interventions may have limited the results. Although this did not appear to influence the face validity of RT as the training was evaluated positively, compliance was high, and the drop out minimal, the fact that both groups made substantial gains across the outcomes makes it impossible to rule out the possibility that improvements were related to the attention and support from this single therapist.
On the other hand, it is possible that the way RT was implemented in this study may have influenced some of the outcome results. The RT group was essentially designed as a control for nonspecific therapist effects including homework practice, but concepts such as the use of an agenda, setting and reviewing homework tasks, and being explicit with treatment rationales, were carried out in both groups when in fact these could be considered key elements of CBT. In addition, relaxation techniques may have a positive effect on stress and sleep, which may in turn improve fatigue. Further research, including a pure relaxation group without CBT type concepts such as homework, as well as a waitlist control, could provide important data in this regard. A further efficacy trial with multiple therapists and with specific measures of the presumed mechanisms of change in the two interventions is also necessary to understand the role of the therapist effect in relation to the possible therapeutic mechanisms.
An additional limitation was that outcome assessment in this study depended on self-rated outcome measures. No objective measures exist for subjectively experienced fatigue, so we chose reproducible measures that are sensitive to change. However, self-reports are amenable to response bias and social desirability effects. Future studies could also assess more objective measures of change such as increases in activity levels and sleep/wake patterns using actigraphs or mental fatigue using reaction time tasks.
Another important issue to consider is whether the gains made in the CBT group over and above the gains made in the RT group are clinically significant. Results from this study have shown that both groups improved on all of the primary and secondary outcomes, with the CBT group improving more on most of the outcome measures. It is possible that RT can be offered by less specialized therapists, which raises questions about what constitutes cost-effective beneficial outcome. However, the study may have been underpowered. At the end of treatment there was a large effect size difference between the two groups, but at follow-up this dropped to a moderate effect size. With a larger group this would have been significant. We based our power analysis on a study of CFS patients who responded less well to the relaxation therapy. In addition, MS is a degenerative condition, so a larger sample may be needed to demonstrate significant effects at follow-up. However, sensitivity analysis suggested that MS disease progression did not affect the pattern of results.
Implications of Findings
Despite the limitations, this study makes a unique contribution to the body of knowledge on effective treatments for MS fatigue. To our knowledge, the present study is the first to compare CBT for MS fatigue with an intervention that controls for factors such as therapist time, support, and attention. It is also the first study to show that CBT improved fatigue in MS patients who were still ambulatory. CBT also had a significant impact on depression, anxiety, and stress. The fact that the RT group also made significant improvements suggests that further controlled evaluations of CBT and RT are needed to define the optimum treatment strategies for MS fatigue, possibly with a larger number of sessions including booster sessions, and a wider range of therapists. A true effectiveness study with non-research clinicians administering the protocols will also be needed to investigate the generalizability of the intervention to clinical practice.
MS fatigue is a multi-factorial symptom and in the long-term, effective clinical practice will require individualized CBT treatment plans rather than adherence to a rigid protocol. This study protocol has provided a basis from which to develop individualized treatment plans. Further research is needed to determine which aspects of CBT are the most effective, the optimal delivery of CBT for MS fatigue, and to carry out cost-benefit analyses of CBT compared with RT.
This study was primarily funded by the Neurological Foundation of New Zealand. Additional funding was obtained from the University of Auckland Staff fund and the J S Say Foundation. We would like to thank the Auckland based MS society, and the Auckland Hospital MS nurses, Justine Simmonds and Kamlesh Nand for their help and support with this study. We would also like to thank Rie Tamagawa, Laura Bogalo, and Bob Chen for their role as assessors in this trial.
This study was approved by the Auckland Human Ethics Committee (AKX/03/03/084).
This study is registered with the Australian Clinical Trials Registry (ACTR).
ACTRN012605000209695.
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Received for publication March 23, 2007; revision received October 6, 2007.
DOI:10.1097/PSY.0b013e3181643065
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