On 2014 Jan 27, Tom Kindlon commented:

References:

[1]. Nijs J, Crombez G, Meeus M, Knoop H, Damme SV, Cauwenbergh V, Bleijenberg G. Pain in patients with chronic fatigue syndrome: time for specific pain treatment? Pain Physician 2012 Sep;15(5):E677-86.

[2]. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME 2011;19(2):59-111. http://www.iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx . Last Accessed: October 2, 2012.

[3]. Jones DE, Hollingsworth KG, Taylor R, Blamire AM, Newton JL. Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. J Intern Med 2010 Apr;267(4):394-401.

[4]. Jones DE, Hollingsworth KG, Jakovljevic DG, Fattakhova G, Pairman J, Blamire AM, Trenell MI, Newton JL. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. Eur J Clin Invest 2012;42:186-94.

[5]. Lane RJ, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry 2003;74:1382-6.

[6]. Knoop H, Stulemeijer M, Prins JB, van der Meer JW, Bleijenberg G. Is cognitive behaviour therapy for chronic fatigue syndrome also effective for pain symptoms? Behav Res Ther 2007;45:2034-43.

[7]. Bleijenberg G, Prins JB, Bazelmans E. Cognitive-behavioral therapies. In Handbook of Chronic Fatigue Syndrome, (ed. L. A. Jason, P. A. Fennell and R. R. Taylor), pp. 493–526. New York, Wiley; 2003.

[8]. Núñez M, Fernández-Solà J, Nuñez E, Fernández-Huerta JM, Godás-Sieso T, Gomez-Gil E. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol 2011 Mar;30(3):381-9.

[9]. Evaluatierapport (2002–2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Dutch language version: http://www.riziv.fgov.be/care/nl/revalidatie/general-information/studies/study-sfc-cvs/pdf/rapport.pdf (Accessed October 2, 2012). French language edition: http://www.riziv.fgov.be/care/fr/revalidatie/general-information/studies/study-sfc-cvs/pdf/rapport.pdf (Accessed October 2, 2012).

[10]. 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;40:1281-7.

On 2014 Jan 27, Tom Kindlon commented:

Pain in patients with chronic fatigue syndrome: more research required to be confident about its etiology and treatment*

{I submitted this letter but it was not accepted for publication]

The review of pain in chronic fatigue syndrome (CFS) by Nijs and colleagues is welcome: as they highlight, pain symptoms are almost universally experienced by patients and are associated with disability levels(1). The importance of pain in the condition is emphasised by the “myalgic” in "myalgic encephalomyelitis" (ME), a term often used synonymously with CFS, and indeed five of the references in the paper have ME in their titles.

The authors recommend that "clinicians should be able to explain to their CFS patients why they are in pain, and such an explanation should be scientifically based". Similarly, to treat the condition, they say "it is crucial to understand the etiology of pain from CFS." Unfortunately, CFS is generally classed as a medically unexplained condition with a lack of consensus on its etiology.

Nijs et al. discuss some of the pathophysiological findings in the condition. However, the review is far from complete in terms of listing all the abnormalities associated with exertion, a frequent cause of pain in the illness(2). While central sensitisation certainly may play a part, peripheral abnormalities appear also to be important. One example that was not mentioned is the abnormal processing of intramuscular pH following exertion(3). These results were subsequently replicated; CFS subjects demonstrated postexercise acid exposure on the order of 50 times higher than normal sedentary controls(4). Moreover, an intriguing study found an association between an abnormal lactate response following an anaerobic threshold exercise test and the presence of enterovirus sequences in muscle in a proportion of CFS patients(5). This also highlights the well-recognised heterogeneity of patients diagnosed with CFS(2), suggesting that one intervention may not be suitable for all. The pain physiology education the authors recommend assumes that central sensitisation characterises and dominates the clinical picture; this is far from universally agreed upon by those in the field.

The other intervention the review highlighted was the form of cognitive behaviour therapy (CBT) that encourages scheduled increases in activity. This recommendation was based on a single paper(6). Nijs et al.’s paper did not clarify that CBT was only found to be "effective" (for pain) for the adult CFS patients that were classed as "recovered" (“recovery” was defined by only a single variable; it is unclear whether this was a post-hoc subgroup analysis). Moreover, the adult study was an uncontrolled trial so improvements reported in the “recovered” subgroup may be due to non-specific factors such as attention by the therapist.

It is also far from clear whether this form of CBT would meet the authors’ own criteria that the explanations given to patients by clinicians are "scientifically based". A manual for this form of CBT explains that patients may be told "the symptoms cannot be explained by persistent virus, nor by dysfunction of the immune system, digestive disorders or other physical causes ... the onset of the fatigue may have been somatic, but that is no longer relevant"(7). There is a lack of robust scientific evidence for these statements.

Nijs et al. did not mention a randomised controlled trial (RCT) comparing a multidisciplinary treatment, combining CBT, graded exercise therapy (GET) and pharmacological therapy, with “usual treatment” (exercise counselling and pharmacological treatment)(8). Unfortunately, there was no waiting list control group but neither intervention was associated with improvements at 12 months compared to baseline in any of the pain measures employed (SF-36 bodily pain, VAS pain intensity and an item determining whether functional impairment was related to pain). In fact, the multidisciplinary treatment (involving CBT and GET) produced statistically significant deteriorations in two of the pain measures.

This raises the important issue of the level of harms associated with graded activity interventions in CFS. An audit of Belgian adult speciality CFS clinics found that following an intervention based on GET and CBT (mean duration: 41 sessions), 31% of patients reported a worsening of their pain as measured by the SF-36 pain subscale(9). Six months following completion, 31% of patients also reported a deterioration in their SF-36 pain scores compared to baseline. More generally, outside of clinical trials, high percentages of patients undertaking programs based on encouraging the scheduling of increased activity or exercise, have reported becoming worse globally following them(2). The “safety profile” appears to be better in research studies. However, the research environment can be somewhat artificial, and differ from routine practice(2). The apparent smaller amount of deteriorations following graded activity/exercise interventions in RCTs may potentially arise from patients not actually increasing their overall activity levels in such trials, perhaps due to a more cautious approach in the research setting(2). For example, a review of three Dutch RCTs of CBT interventions found using actigraphy that, upon completion, activity was not different compared to waiting list controls, a paradoxical result given these programs were based on encouraging increased activity(10). This could occur either through low compliance rates or, alternatively, activity substitution, where participants reduce other activities in their daily lives to compensate for specific activities or exercises (e.g. walking sessions), that are part of a program(2). Moreover, a mediation analysis of the same three CBT studies found that reported changes in fatigue were not due to changes in physical activity levels(10). Similarly, Knoop et al. found in their study that the changes in reported pain were not explained by changes in physical activity, as Nijs et al. themselves reported(1,6). Instead the only relationship found was that a decrease in pain was associated with a decrease in fatigue. Given such data it may be premature to encourage increased total activity.

Clearly more research needs to be conducted to both understand the causes of pain in CFS and to test potential treatments. Given the number of RCTs of nonpharmacological therapies for CFS that have been published, it is disappointing how infrequently pain outcome measures have been used. Hopefully the review by Nijs et al. will help remedy this gap as well as highlighting the need for researchers to try to understand the mechanisms of any change observed.

*possible title – the journal can choose a different title if it prefers

(References continue in next message - this is over the limit)

On 2014 Jan 27, Tom Kindlon commented:

Pain in patients with chronic fatigue syndrome: more research required to be confident about its etiology and treatment*

{I submitted this letter but it was not accepted for publication]

The review of pain in chronic fatigue syndrome (CFS) by Nijs and colleagues is welcome: as they highlight, pain symptoms are almost universally experienced by patients and are associated with disability levels(1). The importance of pain in the condition is emphasised by the “myalgic” in "myalgic encephalomyelitis" (ME), a term often used synonymously with CFS, and indeed five of the references in the paper have ME in their titles.

The authors recommend that "clinicians should be able to explain to their CFS patients why they are in pain, and such an explanation should be scientifically based". Similarly, to treat the condition, they say "it is crucial to understand the etiology of pain from CFS." Unfortunately, CFS is generally classed as a medically unexplained condition with a lack of consensus on its etiology.

Nijs et al. discuss some of the pathophysiological findings in the condition. However, the review is far from complete in terms of listing all the abnormalities associated with exertion, a frequent cause of pain in the illness(2). While central sensitisation certainly may play a part, peripheral abnormalities appear also to be important. One example that was not mentioned is the abnormal processing of intramuscular pH following exertion(3). These results were subsequently replicated; CFS subjects demonstrated postexercise acid exposure on the order of 50 times higher than normal sedentary controls(4). Moreover, an intriguing study found an association between an abnormal lactate response following an anaerobic threshold exercise test and the presence of enterovirus sequences in muscle in a proportion of CFS patients(5). This also highlights the well-recognised heterogeneity of patients diagnosed with CFS(2), suggesting that one intervention may not be suitable for all. The pain physiology education the authors recommend assumes that central sensitisation characterises and dominates the clinical picture; this is far from universally agreed upon by those in the field.

The other intervention the review highlighted was the form of cognitive behaviour therapy (CBT) that encourages scheduled increases in activity. This recommendation was based on a single paper(6). Nijs et al.’s paper did not clarify that CBT was only found to be "effective" (for pain) for the adult CFS patients that were classed as "recovered" (“recovery” was defined by only a single variable; it is unclear whether this was a post-hoc subgroup analysis). Moreover, the adult study was an uncontrolled trial so improvements reported in the “recovered” subgroup may be due to non-specific factors such as attention by the therapist.

It is also far from clear whether this form of CBT would meet the authors’ own criteria that the explanations given to patients by clinicians are "scientifically based". A manual for this form of CBT explains that patients may be told "the symptoms cannot be explained by persistent virus, nor by dysfunction of the immune system, digestive disorders or other physical causes ... the onset of the fatigue may have been somatic, but that is no longer relevant"(7). There is a lack of robust scientific evidence for these statements.

Nijs et al. did not mention a randomised controlled trial (RCT) comparing a multidisciplinary treatment, combining CBT, graded exercise therapy (GET) and pharmacological therapy, with “usual treatment” (exercise counselling and pharmacological treatment)(8). Unfortunately, there was no waiting list control group but neither intervention was associated with improvements at 12 months compared to baseline in any of the pain measures employed (SF-36 bodily pain, VAS pain intensity and an item determining whether functional impairment was related to pain). In fact, the multidisciplinary treatment (involving CBT and GET) produced statistically significant deteriorations in two of the pain measures.

This raises the important issue of the level of harms associated with graded activity interventions in CFS. An audit of Belgian adult speciality CFS clinics found that following an intervention based on GET and CBT (mean duration: 41 sessions), 31% of patients reported a worsening of their pain as measured by the SF-36 pain subscale(9). Six months following completion, 31% of patients also reported a deterioration in their SF-36 pain scores compared to baseline. More generally, outside of clinical trials, high percentages of patients undertaking programs based on encouraging the scheduling of increased activity or exercise, have reported becoming worse globally following them(2). The “safety profile” appears to be better in research studies. However, the research environment can be somewhat artificial, and differ from routine practice(2). The apparent smaller amount of deteriorations following graded activity/exercise interventions in RCTs may potentially arise from patients not actually increasing their overall activity levels in such trials, perhaps due to a more cautious approach in the research setting(2). For example, a review of three Dutch RCTs of CBT interventions found using actigraphy that, upon completion, activity was not different compared to waiting list controls, a paradoxical result given these programs were based on encouraging increased activity(10). This could occur either through low compliance rates or, alternatively, activity substitution, where participants reduce other activities in their daily lives to compensate for specific activities or exercises (e.g. walking sessions), that are part of a program(2). Moreover, a mediation analysis of the same three CBT studies found that reported changes in fatigue were not due to changes in physical activity levels(10). Similarly, Knoop et al. found in their study that the changes in reported pain were not explained by changes in physical activity, as Nijs et al. themselves reported(1,6). Instead the only relationship found was that a decrease in pain was associated with a decrease in fatigue. Given such data it may be premature to encourage increased total activity.

Clearly more research needs to be conducted to both understand the causes of pain in CFS and to test potential treatments. Given the number of RCTs of nonpharmacological therapies for CFS that have been published, it is disappointing how infrequently pain outcome measures have been used. Hopefully the review by Nijs et al. will help remedy this gap as well as highlighting the need for researchers to try to understand the mechanisms of any change observed.

*possible title – the journal can choose a different title if it prefers

(References continue in next message - this is over the limit)