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PACE results undermine the cognitive behavioural model of chronic fatigue syndrome.

Posted by biophile on 08 Aug 2012 at 05:06 GMT

As cost-effectiveness is not treatment effectiveness, it is worth considering the latter with the former.

CBT (and GET, which often accompanies CBT) for CFS are based on the cognitive behavioural model, which purports that "the symptoms and disability of [CFS] are perpetuated predominantly by unhelpful illness beliefs (fears) and coping behaviours (avoidance)". [1] Based on the expected response rates discussed in the original protocol [2] the authors predicted a Number Needed to Treat (NNT) of about 2 for CBT and 2.5 for GET. Their original definition of "clinically important difference", when combined later with the actual trial data, equates to a 9-14 point decrease in fatigue on the Chalder fatigue questionnaire (Likert scoring, range=0=33) and a 20-30 point increase in physical function (SF-36 health survey, range=0-100).

However, the PACE results published by White et al (2011) [3] failed to come close to delivering this expectation. After post-hoc protocol changes during the trial, the new definition of "clinically useful difference" (CUD) equated to either a mere 2 point decrease in fatigue or an 8 point increase in physical function. Even with this major change in goalposts, the NNT for both outcomes simultaneously was about 8 for CBT and 7 for GET. [4] For CBT and GET vs SMC, the net response rate in CUD for self-reported fatigue and/or physical function, was about 11-16% depending on therapy and measure (see Table 3). In other words, only a slim minority of patients "respond" to these therapies and the response is not large. [3] Granted that CBT and GET may help some patients (a finding which should be fairly acknowledged with appropriate caveats), not enough is yet known to predict this response.

Furthermore, the only secondary outcome reported to reach CUD was on the Work and Social Adjustment Scale for the CBT group, which was still only a 3.6 point improvement on a scale of 0-40 points. Although the GET group achieved a statistically significant advantage over SMC on the 6-minute walking test distance (unsurprisingly given that walking was the most commonly chosen exercise in the GET group), it did not reach CUD and remained on par with a range of serious and debilitating medical conditions. [5] This minimal gain questions the general underlying rationale of GET, i.e. symptoms and disability of CFS largely arise from "deconditioning" and "exercise intolerance", while patients should be able to gradually work towards "30-45 minute sessions of moderate intensity physical activity at least five times a week." [6]

The 6MWD also showed no advantage whatsoever for CBT over SMC, despite self-reported improvements in physical function. [3] This finding is unsurprising considering a meta-analysis of 3 previous CBT trials reported that therapy did not improve objective measures of overall physical activity according to actigraphy. [7] Coincidently, although PACE had the necessary equipment for this outcome and took baseline measurements, they failed to take follow-up measurements, claiming that (a watch-sized device worn around the ankle for a week) was "too great a burden at the end of the trial". [8]

The PACE results suggest that CBT and GET can encourage small to "moderate" improvements in self-reported fatigue and/or physical function for a slim minority of patients meeting a heterogeneous criteria for CFS, one which stipulates that fatigue must be the only main symptom. These results do not apply to severely affected patients and are a best case scenario, may not translate well into routine clinical practice outside a research trial, cannot support a blanket application of these therapies, and do not justify an entire model devoted primarily to presumed cognitive and behavioural factors. All this is before addressing the numerous potential methodological concerns which have been charged against the trial.

The lead author and a principal investigator of the PACE Trial, Professor Peter White, is a notable proponent of the biopsychosocial model of illness, which he has applied to CFS in particular throughout his career. White has even claimed that the biomedical approach to helping patients (in general) improve their health and reduce their disability, is akin to travelling up a "blind alley". [9] However, the professional International Association for CFS/ME, which has no problem with psychotherapeutic or behavioural interventions per se, have expressed serious concern over the causal model associated with CBT and GET for CFS, which predicts that these therapies can "reverse" or even cure the disease. [10]

In conclusion, it would be rather unfortunate for millions of patients worldwide if this presentation of CFS, as essentially a "functional" cognitive-behavioural illness, has itself resulted in a relatively dead-end approach to CFS which has been overstated. Was it any coincidence that around the same time the first paper on the PACE Trial results was being submitted and peer-reviewed for publication in the Lancet (many months after the results were known to those who had access to them), the MRC in the UK announced a call for alternative research proposals into the causes and mechanisms of CFS (after decades of negligible funding to biomedical research)? [11]. Before the end of that year, it had awarded more than £1.6m to projects covering the biological footprints of fatigue, pathogenesis of autonomic dysfunction, aberrant mitochondrial function and cytokine production, and an interferon-alpha based immunological model. [12] This historical shift in direction for the MRC, coinciding with the PACE Trial results, suggests a loss of confidence in the cognitive behavioural model of chronic fatigue syndrome.


[1] Manual For Therapists: Cognitive Behavioural Therapy for CFS/ME. Mary Burgess, Trudie Chalder.

[2] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. 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. BMC Neurol. 2007 Mar 8;7:6. http://www.biomedcentral....

[3] White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; [PACE trial management group]. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. Epub 2011 Feb 18. DOI: 10.1016/S0140-6736(11)60096-2 http://www.ncbi.nlm.nih.g...

[4] Glickman-Simon R, Tenkku LE. Carpal tunnel syndrome, low back pain, chronic fatigue syndrome, preventing preeclampsia, preventing complex regional pain syndrome. Explore (NY). 2012 Jan;8(1):65-7.

[5] Zugck C, Krüger C, Dürr S, Gerber SH, Haunstetter A, Hornig K, Kübler W, Haass M. Is the 6-minute walk test a reliable substitute for peak oxygen uptake in patients with dilated cardiomyopathy? Eur Heart J. 2000 Apr;21(7):540-9. http://eurheartj.oxfordjo...

[6] Manual For Therapists: Graded Exercise Therapy for CFS/ME. Bavinton J, Darbishire L, White PD, on behalf of the PACE trial management group.

[7] Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Aug;40(8):1281-7. Epub 2010 Jan 5. http://www.ncbi.nlm.nih.g...

[8] Response to comments on 'Protocol for the PACE trial'. | Peter White (2008-07-28 12:24) | http://www.biomedcentral....

[9] Aziz Sheikh. Biopsychosocial Medicine. J R Soc Med. 2005 September; 98(9): 431–432. http://www.ncbi.nlm.nih.g...

[10] IACFS/ME Statement on the PACE Trial: The Issue of Illness "Reversal" | February 24, 2011 |

[11] MRC invests £1.5m to encourage further CFS/ME research | 27 January 2011 |

[12] Medical Research Council announces ME/CFS research projects worth £1.6m | December 21, 2011 | http://www.meassociation....

Competing interests declared: Long-term ME/CFS patient.

RE: PACE results undermine the cognitive behavioural model of chronic fatigue syndrome.

biophile replied to biophile on 08 Aug 2012 at 10:43 GMT

Additional notes for the above comment:

It is important to point out that the authors' definition of "clinically useful difference" (CUD = 0.5 SD baseline score) was a minimal threshold and a dichotomous outcome. The above comment did not mean to imply that the only difference between both CBT and GET vs SMC (in terms of self-reported fatigue and physical function) was an actual 2 point decrease in fatigue and/or 8 point increase in physical function for only about 11-16% of participants, depending on the therapy and measure. Unless a select few patients are improving drastically after CBT and GET, the data on group average continuous scores probably suggests that those who passed CUD threshold in the CBT and GET groups generally improved somewhat more than those who passed CUD threshold in the SMC group.

When compared to the SMC group in continuous scores, the CBT group meet CUD threshold for fatigue (+3.4 points) but not for physical function (+7.1 points), while the GET group met CUD threshold for both fatigue (+3.2 points) and physical function (+9.2 points). This was the basis for the authors' interpretation that CBT and GET have "moderate" effects. However, as noted in the previous comment, the authors' original expectations and goalposts were much more optimistic before post-hoc changes to the protocol. The standard deviation of baseline scores would have been artificially lowered by the recruitment process, as both mildly and severely affected patients were excluded from the trial. A more homogeneous patient cohort at baseline, in terms of symptom/disability severity, means a lower CUD threshold which is therefore easier to surpass even with minimal improvements.

The interventions studied in the PACE Trial were unblinded to both patients and therapists, and therefore these results should be afforded similar caution given to other unblinded trials. The nature of the reported improvements are uncertain, particularly when considering the general lack of objective measures in the trial, and the poor outcomes in terms of overall service usage/costs, employment losses, welfare benefits or other financial payments. White et al (2011) report that initial expectations were low in the CBT and SMC groups and high in the APT and GET groups, and point out that expectations are therefore an unlikely confounder as CBT demonstrated advantage while APT did not. However, missing from their discussion was consideration for the differences in implied prognosis in the therapy manuals during the course of the trial, for both patients and therapists. CBT and GET manuals are more optimistic than the SMC and APT manuals. The cognitive behavioural model also questions the accuracy of patients' perceptions and cognitions about their own illness and aims to directly modify these.

Competing interests declared: Long-term ME/CFS.