Pain in CFS: response to rehabilitative treatments in the PACE Trial

[Firestormm]

Psychol Med. 2013 Aug 23:1-8. [Epub ahead of print]

Pain in chronic fatigue syndrome: response to rehabilitative treatments in the PACE trial.

Bourke JH, Johnson AL, Sharpe M, Chalder T, White PD.

Source

Centre for Psychiatry, Wolfson Institute for Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.

Abstract

BACKGROUND:

Pain is a common symptom of chronic fatigue syndrome (CFS).

We investigated the effects of the treatments used in the PACE trial [cognitive behavioural therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy (APT) and specialist medical care (SMC)] on pain in CFS.

METHOD:

We compared pain outcomes including individual painful symptoms, taken from the CDC criteria for CFS and co-morbid fibromyalgia. We modelled outcomes adjusting for baseline variables with multiple linear regression.

RESULTS:

Significantly less frequent muscle pain was reported by patients following treatment with CBT compared to SMC (mean difference = 0.38 unit change in frequency, p = 0.02), GET versus SMC (0.42, p = 0.01) and GET versus APT (0.37, p = 0.01).

Significantly less joint pain was reported following CBT versus APT (0.35, p = 0.02) and GET versus APT (0.36, p = 0.02).

Co-morbid fibromyalgia was less frequent following GET versus SMC (0.03, p = 0.03).

The effect sizes of these differences varied between 0.25 and 0.31 for muscle pain and 0.24 and 0.26 for joint pain.

Treatment effects on pain were independent of 'change in fatigue'.

CONCLUSIONS:

CBT and GET were more effective in reducing the frequency of both muscle and joint pain than APT and SMC.

When compared to SMC, GET also reduced the frequency of co-morbid fibromyalgia; the size of this effect on pain was small.

PMID: 23967878
[PubMed - as supplied by publisher]

 

[heapsreal]

I would like to see dr dan peterson's specialist medical care (SMC) versus the pace trial.

 

[Bob]

Participants who experienced increased levels of pain after treatment with CBT/GET, such that pain was considered to be their 'main symptom', were then reported to be 'recovered' because they were no longer eligible for an Oxford diagnosis of CFS.

(No sign of the long-term follow-up paper yet!)

 

[Simon]

Commentary: small effect of PACE Trial CBT & GET on pain

This study used data from the large (n=640) PACE Trial to measure the impact of CBT and Graded exercise on pain. The main trial itself found a moderate effect of CBT and GET on self-reported fatigue and function.

The study looked at muscle and joint pain using the CDC CFS symptom inventory which measures both frequency and severity of pain in the last month. It also looked at fibromyalgia status.

Despite the data coming from a £5 million pound taxpayer-funded trial, this paper is locked behind a paywall and costs patients £30 to access. So I can only comment on the abstract for now.

What they report in the abstract:
Let's start at with the most important positive finding - the treatment 'effect size':
[Broadly, an effect of between 0.2 and 0.4 is small, 0.4-0.6 is moderate, above 0.6 is large and the maximum effect size can be bigger than 1.0. Below 0.2 is trivial.]

• For muscle pain severity for CBT & GET (vs APT or SMC control) effect sizes ranged from 0.25 to 0.31. These are all small.
• For joint pain severity effect sizes were 0.24 and 0.26. These are also small.
• Only GET improved fibromyalgia status and the effect was small at best.

This means that neither CBT nor GET were even moderately effective at reducing pain in CFS.

edit: Here's what an effect size of 0.27 looks like (typical in this study). The graph shows the distributions of control and treatment groups where the treatment has an effect size (cohen's d) of 0.27. The shaded pink area is the overlap between the two groups. This shows the treatment group with a slightly lower pain frequency than the control group - but there isn't a lot in it.

Treatment effects on pain were independent of ‘change in fatigue’.

This is odd: you might expect pain to improve with an overall improvement in the illness, yet gains in pain were not linked to improvement in fatigue.

What they don't report in the abstract:

• They don't report any change in muscle or joint pain severity, despite having the data -which makes it likely that they found no reduction in pain severity
• For muscle pain frequency, CBT was superior to SMC but not superior to APT (pseudo-pacing)
• For joint pain frequency, neither CBT nor GET was any better than APT
• CBT had no effect on fibromyalgia status, and GET only improved fibomyalgia vs SMC, not vs APT

Summary
Patchy and small effect of CBT/GET on muscle and joint pain frequency. Probably no effect on pain severity (since data was collected but the analysis was not reported). Minimal effect on fibromyalgia status and any improvements in pain were unrelated to improvement in fatigue.

This is perhaps a more complete view then the authors' conclusion in their abstract:

Conclusions
CBT and GET were more effective in reducing the frequency of both muscle and joint pain than APT and SMC.

 

[biophile]

What Simon said. I would also like to see the binary outcomes for a "clinically useful difference", as it may be somewhat useful to a slim minority of broadly-defined CFS patients (as it may be for self-reported fatigue). But ...

*cough* non-blinded trial testing therapies which aimed to alter participants' perceptions about symptoms *cough*
For all we know, open-label trials on homeopathy would find a similar effect.
Still waiting for the papers on predictors and mediators, as well as long-term followup.

heapsreal. Re "I would like to see dr dan peterson's specialist medical care (SMC) versus the pace trial."
Good idea, but this would not have been allowed, as SMC did not allow any exotic treatments, only routine care.

 

[Sasha]

Simon - thanks for that analysis. Are the planned analyses publicly available so we can compare what's being reported and what was planned for analysis of pain?

 

[alex3619]

The placebo effect is of only limited (if any) use in most circumstances. However with respect to pain it may be powerful. Given what we know about PACE, its lack of blinding etc., then they need a very strong result to say with any certainty that its not entirely the placebo effect. They didn't get it. Also severity of pain is critical, not just frequency, though in my own case (anecdotal) severity and frequency do seem to be related.

 

[Esther12]

Participants who experienced increased levels of pain after treatment with CBT/GET, such that pain was considered to be their 'main symptom', were then reported to be 'recovered' because they were no longer eligible for an Oxford diagnosis of CFS.

I assume that they included the 'recovered' patients in this analysis?

(No sign of the long-term follow-up paper yet!)

We don't know that actually happened to anyone though, do we, even if their criteria makes it possible? My standards for PACE are pretty much rock bottom, but it would still be pretty shocking if they allowed that.

 

[Bob]

Participants who experienced increased levels of pain after treatment with CBT/GET, such that pain was considered to be their 'main symptom', were then reported to be 'recovered' because they were no longer eligible for an Oxford diagnosis of CFS.

I assume that they included the 'recovered' patients in this analysis?

We don't know that actually happened to anyone though, do we, even if their criteria makes it possible? My standards for PACE are pretty much rock bottom, but it would still be pretty shocking if they allowed that.

I posted that question in annoyance, and hadn't thought it through!
Some of the 'recovered' participants perhaps would have made the most significant improvements, so I'm sure that they would have included them.
Although, if this analysis was post-hoc, there may have been some statistical jiggery-pokery at play. (But still only a small effect size.)

 

[biophile]

The composite definition of "recovery" had 3 criteria, which included a CGI score of much better or very much better. Although not an indication of complete recovery, it seems unlikely that someone would score that if pain became significantly worse. However, that may not apply to the other two criteria i.e. Oxford criteria where pain is not allowed to be the main symptom, and within "normal" *cough* range of fatigue and physical function which was the first criteria.

 

[WillowJ]

The composite definition of "recovery" had 3 criteria, which included a CGI score of much better or very much better. Although not an indication of complete recovery, it seems unlikely that someone would score that if pain became significantly worse. However, that may not apply to the other two criteria i.e. Oxford criteria where pain is not allowed to be the main symptom, and within "normal" *cough* range of fatigue and physical function which was the first criteria.

I don't know; if their fatigue was less and their pain was worse, but their sleep (and depression if they had that) was better (and they'd gotten a diagnosis, right or wrong, and had someone "nice" to listen to them), and their physical function was unchanged or only 1 score (5 pts on a 5-pts scale) less (and was 60 or 65), they might say "much better".

they might say "much better" solely from having someone "nice" to listen to them and try to help in some way even if completely ineffective, especially if they've never had that before.

 

[Dolphin]

Anyone else think it's a little suspicious that they only concentrated on muscle pain and joint pain given the table below. This is all the data we got for the other three pain symptoms.

Looking at tender lymph nodes, for example, the raw changes in percentages were:
-8% (APT),
-4% (CBT),
0% (GET)
and
-7% (SMC).

Or in percentage terms of those with the symptom at baseline:
26.3% reduction (APT),
10.7% reduction (CBT),
1% reduction (GET)
and
22.1% reduction (SMC only).

The results for sore throat, although not as clear cut, also don't suggest much difference or evidence for CBT and GET (headache is intermediary)

All they say is:
"We chose muscle pain and joint pain as individual symptom outcomes, before analysis of outcome data, since these were the most commonly reported [symptoms] at baseline".
(note: protocol doesn't mention they are going to do this, so there is a chance they may have had a feel for how things were going, or know from other situations)

Table 2. Presence of individual symptoms, valid % (n)
APT APT CBT CBT GET GET SMC only SMC only
Baseline 52 weeks Baseline 52 weeks Baseline 52 weeks Baseline 52 weeks
Symptom n=159 n=151 n=161 n=145 n=160 n=144 n=160 n=149
Muscle pain 71 (113) 60 (91) 64 (102) 50 (73) 71 (114) 50 (72) 72 (115) 60 (89)
Joint pain 52 (84) 49 (74) 50 (81) 34 (49) 51 (81) 39 (56) 52 (83) 45 (67)
Headache 37 (59) 31 (47) 39 (63) 28 (40) 37 (59) 29 (42) 36 (58) 34 (50)
Sore throat 32 (51) 31 (50) 33 (53) 28 (41) 29 (46) 31 (44) 30 (48) 27 (40)
Tender lymph nodes 31 (50) 23 (35) 32 (51) 28 (41) 29 (46) 29 (41) 32 (51) 25 (37)

---
Another point for what it's worth: the numbers whose data we don't have are:
APT: 8,
CBT: 16
GET: 16
SMC only: 11
i.e. the biggest numbers are for CBT and GEt. One wonders what their data might be like.

 

[Dolphin]

An aside really - this isn't important.

They say they are using the Wolfe et al. (2010) Fibromyalgia criteria at least three times. This doesn't make much sense given this trial started in 2005!

Also, the Wolfe et al. (2010) criteria requires counting somatic symptoms http://www.ncbi.nlm.nih.gov/pubmed/20461783 but there is no mention of them doing this.

The protocol (http://www.biomedcentral.com/1471-2377/7/6) tells us they planned to use:

4. Presence or absence of fibromyalgia (using chronic widespread pain criteria only and not tender points) [41]

Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, al. : The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
Arthritis Rheum 1990, 33:160-172.

This matches the description in the text so is presumably what they used.

 

[Dolphin]

(Very minor point: this doesn't matter much as it wasn't statistically significant)
For anyone who has the full paper:
I'm a little confused by Table 3 (presence of Fibromyalgia diagnostic criteria):
This deterioriates for CBT:
Baseline: 17% (28)
52 weeks: 20% (29)

while improves a tiny bit for APT:
Baseline: 25% (39)
52 weeks: 24% (36)

so the comparison in the second column should be opposite compared to GET i.e. GET > APT > CBT. So if GET vs APT is positive, then CBT vs APT should be negative (albeit not statistically significant).

 

[Dolphin]

(In case anyone missed it)
The journalist, David Tuller DrPH, on Wednesday posted a substantial piece on the PACE Trial:

TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study
http://www.virology.ws/2015/10/21/trial-by-error-i/

There's an introduction and summary at the start if you don't want to take on the whole thing.

It's being discussed in this PR thread:
http://forums.phoenixrising.me/inde...he-pace-chronic-fatigue-syndrome-study.40664/

ME Network have also posted their own summary piece:
http://www.meaction.net/2015/10/21/david-tuller-tears-apart-pace-trial/

Part two of David Tuller's piece is at:
http://www.virology.ws/2015/10/22/trial-by-error-ii/

Cort Johnson has done one of his easy-to-read pieces on it here:

http://www.cortjohnson.org/blog/201...-chronic-fatigue-syndrome-pace-cbt-get-trial/