"Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with CFS..."

[Kyla]

http://www.biomedcentral.com/1471-2431/15/117
(open access)

Research article
Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial
Even Fagermoen12*, Dag Sulheim34, Anette Winger5, Anders M. Andersen6, Johannes Gjerstad78, Kristin Godang9, Peter C. Rowe10, J. Philip Saul11, Eva Skovlund1213 andVegard Bruun Wyller114 *Corresponding author: Even Fagermoen feef@online.no


BMC Pediatrics 2015, 15:117 doi:10.1186/s12887-015-0428-2

The electronic version of this article is the complete one and can be found online at:http://www.biomedcentral.com/1471-2431/15/117


Received: 7 September 2014
Accepted: 20 August 2015
Published: 10 September 2015
© 2015 Fagermoen et al.


Abstract
Background
Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha 2A –adrenoceptor agonist clonidine.

Methods
A total of 176 adolescent CFS patients (12–18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model.

Results
A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period.

Conclusions
Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.

Trial registration
Clinical Trials ID: NCT01040429, date of registration 12/28/2009.

 

[A.B.]

How many clonidine studies do we need to have before Wyller accepts that it's not a generally useful medication?

 

[Valentijn]

Funny, I use an ADRA2A antagonist to help with my OI, not an ADRA2A agonist. Did they have some reason to think that Norepinephrine was too high in their patients to start with?

 

[Marky90]

How many clonidine studies do we need to have before Wyller accepts that it's not a generally useful medication?

Wyller believes ME/CFS is due to the brain being in a continuous stress-response, he don`t seem to change his opinion, even in light of the haukeland studies..

 

[DeGenesis]

Funny, I use an ADRA2A antagonist to help with my OI, not an ADRA2A agonist. Did they have some reason to think that Norepinephrine was too high in their patients to start with?

This same group did a study which found that CFS patients had higher plasma norepinephrine levels as compared to controls. Of course higher levels does not mean too high for that specific patient population, which I think is what you're saying, and is exactly the same conclusion they came too in their previous study:

"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."

Why they thought is would work this time, as A.B. points out, is a mystery.

For a long time I thought clonidine would bring benefits to myself, but I was very wrong. Unfortunately, I can't import yohimbine into Canada. I've been very lucky with mirtazapine, also an alpha-2 antagonist, but doubtless this drug has more side-effects.

 

[Sushi]

Funny, I use an ADRA2A antagonist to help with my OI, not an ADRA2A agonist.

Me too. I guess this explains why clonidine was one of the worst drugs (for me) that I've ever tried.

This same group did a study which found that CFS patients had higher plasma norepinephrine levels as compared to controls.

And I did well with a norep reuptake inhibitor.

 

[DeGenesis]

And I did well with a norep reuptake inhibitor.

I think you can have high norepinephrine and still do well on a drug that raises norepinephrine. I tested high in urinary catecholamines (I admit I have no idea what the implications of this test are vs. testing plasma norephinephrine) and I do well on bupropion (an NRI) and mirtazapine (an alpha-2 antagonist, the opposite of clonidine). I just happen to tolerate the latter better.

FWIW, I'm not recommending anyone go out and blindly take mirtazapine. I seem to recall that Alex had a dangerous experience with it.

 

[Sushi]

I tested high in urinary catecholamines (I admit I have no idea what the implications of this test are vs. testing plasma norephinephrine)

This tests what you are excreting but that doesn't necessarily reflect the levels in the synapses.

 

[Valentijn]

Unfortunately, I can't import yohimbine into Canada. I've been very lucky with mirtazapine, also an alpha-2 antagonist, but doubtless this drug has more side-effects.

Are you able to cross the border with it? I can't buy Yohimbine in the Netherlands, but it's legal to bring my personal stash in with me.

 

[Valentijn]

I think you can have high norepinephrine and still do well on a drug that raises norepinephrine.

Mine was a bit low in urine, and quite a bit lower in two blood tests a year or two apart. There does seem to be a subsection of ME patients who are high, but it might be a relatively small minority.

 

[Grigor]

I've now tried Clonidine for 2 days. I can only take 1/16th of a 0.1 cause I'm too sensitive .

Anyways while on it it's okish. I'm more tired and wasted but standing does seem to go easier. But around 7 PM I feel terrible. Like my body is inbetween my old state and the Clonidine state. No control over my body etc. Hope this will change.
Clonidine is the first meds I try that gives me some kind of positive effect but the evening part freaks me out a bit to be honest.