Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome

[A.B.]

Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome

Conclusions and Relevance
Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus-pituitary-adrenal axis function, cognitive impairment, and large activity reduction, but not with common microorganisms. Low-dose clonidine attenuates sympathetic outflow and systemic inflammation in CFS but has a concomitant negative effect on physical activity; thus, sympathetic and inflammatory enhancement may be compensatory mechanisms. Low-dose clonidine is not clinically useful in CFS.

http://archpedi.jamanetwork.com/article.aspx?articleid=1827799

 

[anciendaze]

To reiterate: many patients, particularly adolescents, show orthostatic hypotension. Clonidine is commonly used to treat hypertension, high blood pressure. This should make clonidine contraindicated. This is also a major problem with CFS patients tolerating common antidepressants.

Adolescent CFS is associated with enhanced
sympathetic nervous activity, low-grade systemic inflammation,
attenuated hypothalamus-pituitary-adrenal axis function, cognitive
impairment, and large activity reduction, but not with common
microorganisms.

My bolding. If EBV is not a common microorganism, what is? (In reference to this report.)

 

[CBS]

The principle investigator for this study is Vegard Bruun Wyller. He was a key player in de-funding the Rituximab phase III study in Norway, likely because he felt that it would draw attention and money away from his pet hypothesis, that CFS is a minor neurological signaling disorder. Two items are of note with this study; 1) it was a colossal failure - chlonidine actually decrease activity in CFS patients (no small feat considering how hard it is for us to be active) and 2) Peter Rowe was a collaborator and turned out to be just as wrong as Wyller.

They should however receive some credit for actually publishing a study that so definitively disproved their presumptions about CFS. Looks like it's back to the drawing board for these two. Now, if they'll just stay out of the way of Fluge and Mella.


Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue SyndromeA Combined Cross-sectional and Randomized Clinical Trial ONLINE FIRST
Dag Sulheim, MD1,2; Even Fagermoen, MD3,4; Anette Winger, RN, MA3,5; Anders Mikal Andersen, BSc6; Kristin Godang, BSc7; Fredrik Müller, MD, PhD8; Peter C. Rowe, MD, PhD9; J. Philip Saul, MD10; Eva Skovlund, PhD11,12; Merete Glenne Øie, PhD13,14; Vegard Bruun Wyller, MD, PhD1,15,16

[-] Author Affiliations 1Department of Paediatrics, Oslo University Hospital, Oslo, Norway
2Department of Paediatrics, Lillehammer County Hospital, Lillehammer, Norway
3Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway
4Department of Anesthesiology and Critical Care, Oslo University Hospital, Oslo, Norway
5Institute of Nursing Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway
6Department of Pharmacology, Oslo University Hospital, Oslo, Norway
7Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital Rikshospitalet, Oslo, Norway
8Department of Microbiology, Oslo University Hospital, Oslo, Norway
9Department of Pediatrics, the Johns Hopkins University School of Medicine, Baltimore, Maryland
10Department of Pediatrics, Medical University of South Carolina, Charleston
11School of Pharmacy, University of Oslo, Oslo, Norway
12Norwegian Institute of Public Health, Oslo, Norway
13Department of Psychology, University of Oslo, Oslo, Norway
14Innlandet Hospital Trust, Lillehammer, Norway
15Division of Medicine and Laboratory Sciences, Medical Faculty, University of Oslo, Oslo, Norway
16Department of Paediatrics, Akershus University Hospital, Nordbyhagen, Norway

 

[A.B.]

When I read what Clonidine was used for, I thought that it would make patients worse, and so it did. It's not unsurprising either, at least for us patients, but doctors often seem to have views on CFS that are unrelated to reality. To their credit, they admitted that Clonidine made patients worse, so they do seem to be genuinely interested in reality.

If only they understood that CFS isn't a motivational, mood, or belief problem, and that reduced activity is a survival strategy enforced by the body struggling with a serious underlying problem.

 

[CBS]

"He (Wyller) said the study (Fluge and Mella) does not necessarily indicate that the disease is due to autoimmune mechanisms.- This is only one of several possible hypotheses. For example, other data have shown that the autonomic nervous system plays a role. Phenomena associated with central nervous system may provide just such immunological changes that we see in ME patients . Also hormonal and psychological factors influence the clinical picture , which is complex and multifactorial , says Bruun Wyller ."

My bold and my underline.

 

[CBS]

...so they do seem to be genuinely interested in reality.

Not so fast:

"Wyller from child clinic at the hospital understand the disease from a stress response hypothesis, and recommend treatment with cognitive behavioral therapy and graded exercise. The criteria for diagnosis is wide .Wyller believe that anyone who is tired long enough and have nothing else , they have this. Wyller recommended in children and adolescents taking the Lightning Process course ( LP ) in Active process "because many items are well aligned with what we otherwise know of the condition ."LP instructor Live Landmark in Active Process writes on his blog : "All participants must be convinced that they know that we teach in a way where they can be turn or affect a condition that can be caused or maintained by stress. »"

 

[A.B.]

Not so fast:

Point taken. It makes sense that systematic incompetence would stem from incorrect assumptions given undue credit.

 

[Dolphin]

The protocol is here in case it is of use/interest to anybody:
http://www.oslo-universitetssykehus...attelsessyndrom/NorCAPITAL final protocol.pdf

 

[kaffiend]

I have taken Tenex (guanfacine) for several years. It's a pre-synaptic alpha2A agonist similar to clonidine but it's more centrally acting. It has worked quite well for the "wired" part of the the wired/tired feeling. There is also a lot of research showing how guanfacine can improve working memory circuits in the brain. Shire has actually made an extended release version and it's now FDA approved as a non-stimulant treatment for ADHD.

I also recall the Lights' research showing up regulation of alpha2A receptors after exercise.

 

[Soundthealarm21]

I take clonidine daily and it is a very helpful medication (I use it solely for sleep, nothing else). When i'm going through a bad detox it is the one sure thing that will knock me out.


Edit: I have higher blood pressure (Not high, but on the higher side of normal)

 

[LaPerla]

Norwegian study does not support "sustained arousal hypothesis"?

CONCLUSIONS
ABSTRACT | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES

Adolescent CFS is associated with enhanced sympathetic nervous activity, attenuated hypothalamus-pituitary-adrenal axis, low-grade systemic inflammation, slight cognitive impairment, and large activity reduction, but not with common microorganisms. Sympathetic enhancement might cause inflammation, but neither sympathetic enhancement nor inflammation appears to contribute to physical disability or fatigue. Low-dose clonidine is not a clinically useful therapy in adolescent CFS; rather, it appears that the autonomic and inflammatory processes that clonidine blocks may have beneficial effects.

Link to the study:

http://bit.ly/LsC5Wy

 

[Bob]

Hi LaPerla. A big welcome to the forum, and thank you for posting this information.
Just to let you know, some discussion has already taken place on the forum about this paper:
http://forums.phoenixrising.me/inde...in-adolescent-chronic-fatigue-syndrome.28043/

 

[Sushi]

@LaPerla @Bob

Note: These two threads are now merged

 

[LaPerla]

Thanks!
I'm sorry, I did not notice the first discussion about the paper

 

[Dolphin]

I just read this paper. I thought the authors were fair in their reporting. It was good to have the e-supplement with all the extra info that didn't fit in the main paper (it would be good if more investigators did this).

In terms of the number of steps per day, the healthy controls had an average of 10 302.

It was more a case of the placebo group increasing their steps than the active group decreasing.

Clonidine:
Baseline: 4670
8 weeks (end of trial): 4631
30 weeks (they were long off the drug by this time): 4682

Placebo group:

Baseline: 4564
8 weeks (end of trial): 5212
30 weeks (they were long off the drug by this time): 4652

Though they did find:

Clonidine plasma concentration was negatively associated with the number of steps per day and positively associated with the fatigue score (Supplement [eTable 10]). No other dose-response relationships were detected apart from a negative association between the estimated steady-state concentration and the insomnia score (ie, insomnia problems increased with concentrations).

 

[Dolphin]

There was a good adherence rate (they counted the tablets left at the end):

The mean index of adherence was 93% (clonidine group) and 92% (placebo group). At week 8 in the clonidine group, the mean plasma concentration of clonidine was 0.24 μg/L. The estimated mean steady-state concentration (trough value) was 0.23 μg/L.

The results of per-protocol analyses were closely similar to the modified intention-to-treat analyses (Supplement [eTable 9]).

 

[Dolphin]

Adverse Events
In the clonidine group, one patient fainted and another patient was found to have a peptic duodenal ulcer immediately after the intervention period. Sleepiness and dizziness when rising were significantly more common in the clonidine group, but there was no significant difference in the total number of self-reported adverse effects (Supplement [eTable 11]).

 

[Dolphin]

Sympathetic Nervous Activity
Compared with the controls, patients with CFS had increased levels of plasma norepinephrine, as well as a higher heart rate (supine and upright) and heart rate responsiveness, indicating sympathetic enhancement. Increased plasma norepinephrine is a conspicuousf inding, confirming previous results,11 and is consistent with a report of high plasma neuropeptide Y levels.41 Sympathetic enhancement might result from physical deconditioning. In the present study, however, neither plasma norepinephrine level nor heart rate responsiveness was associated with the number of steps per day in patients with CFS (Supplement [eTable 12]).

 

[Dolphin]

Of the 120 patients, 88 individuals (73.3%) satisfied the Fukuda criteria from the International Chronic Fatigue Syndrome Study Group,1 and 49 patients (40.8%) had depressive symptoms indicating a possible comorbid mood disorder.40

No differential outcome related to the 2 predefined subgroups (adherence to the Fukuda criteria and presence of depressive symptoms) was found.

The prevalence of comorbid depressive symptoms among patients with CFS was higher than in a comparable study.49 It is possible that we included some patients with primary depression rather than CFS; ideally, a formal psychiatric interview should have been conducted. However, a more likely explanation is low discriminant validity of the applied depression inventory, because several single items assess symptoms that are common in both depression and CFS.40

 

[CBS]

I just read this paper. I thought the authors were fair in their reporting. It was good to have the e-supplement with all the extra info that didn't fit in the main paper (it would be good if more investigators did this)....

Hi Dolphin,

Thanks for this series of posts. I too have found Dr. Wyller to be professional in how he presents his research. Nearly three (?) years ago we had an extended exchange during which he provided me a copy of the entire NorCal protocol. During the exchange, I raised a number of questions about alternative explanations if the NorCal project failed to support his hypothesis (which really can be boiled down to viewing CFS as relatively minor signaling disorder that involves the HPA axis).


He does use a fairly relaxed set of criteria for patient selection and I doubt that this works in his favor (even though I disagree with his hypothesis). On the other side of this issue, I personally feel that the criteria he uses reflects his view of CFS as a less serious condition. That said, even using his less selective criteria, he does have some very interesting findings in two previous study which included significantly lower levels of ADH in patients compared to controls.

Acta Pædiatrica 2010 99, pp. 770–773

Hormonal alterations in adolescent chronic fatigue syndrome

Vegard Bruun Wyller, Johan Arild Evang, Kristin Godang, Kari K. Solhjell, Jens Bollerslev

Abstract

Aim: The chronic fatigue syndrome is associated with alterations in the hypothalamus-pituitaryadrenal
axis and cardiovascular autonomic nervous activity, suggesting a central dysregulation. This
study explored differences among adolescent chronic fatigue syndrome patients and healthy controls
regarding antidiuretic hormone, the renin-angiotensin-aldosterone-system, sex hormones and cardiac
peptides.

Methods: We included a consecutive sample of 67 adolescents aged 12–18 years with chronic
fatigue syndrome diagnosed according to a thorough and standardized set of investigations, and a
volunteer sample of 55 healthy control subjects of equal gender and age distribution. Hormones were
assayed with standard laboratory methods.

Results: Among patients, plasma antidiuretic hormone was significantly decreased and serum
osmolality and plasma renin activity were significantly increased (p <= 0.001). Serum concentration of
aldosterone, cortisol, NT-proBNP and sex hormones were not significantly different in the two groups.

I have taken a very close look at this earlier study and I would argue that due to the skewed nature of his findings within the patient group, he likely has two sub-groups, a group that many on this forum would describe as having ME and another group which may be defined "non-ME". If the subject group in this previous study is composed of two subgroups and only one of them contributed all of the differences in ADH levels, the "ME" patient group would have to had dramatically lower ADH levels in order for this difference to have remained evident (at a p <= 0.001 level!), even after having been diluted by the non-"ME" patients.


At this point, the question for me is, "what does Wyller now do with the findings of a very large and expensive study that have nor supported his hypothesis?" I find his suggestion that some combination of deconditioning and/or cohort contamination with depression less than encouraging.

Shane