Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome, 2014, Sulheim et al

[ScoutB]

Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome

Spoiler: Authors

Sulheim, Dag; Fagermoen, Even; Winger, Anette; Andersen, Anders Mikal; Godang, Kristin; Müller, Fredrik; Rowe, Peter C.; Saul, J. Philip; Skovlund, Eva; Øie, Merete Glenne; Wyller, Vegard Bruun

Abstract

Importance Chronic fatigue syndrome (CFS) is a disabling condition with unknown disease mechanisms and few treatment options.

Objective To explore the pathophysiology of CFS and assess clonidine hydrochloride pharmacotherapy in adolescents with CFS by using a hypothesis that patients with CFS have enhanced sympathetic activity and that sympatho-inhibition by clonidine would improve symptoms and function.

Design, Setting, and Participants Participants were enrolled from a single referral center recruiting nationwide in Norway. A referred sample of 176 adolescents with CFS was assessed for eligibility; 120 were included (34 males and 86 females; mean age, 15.4 years). A volunteer sample of 68 healthy adolescents serving as controls was included (22 males and 46 females; mean age, 15.1 years). The CSF patients and healthy controls were assessed cross-sectionally at baseline. Thereafter, patients with CFS were randomized 1:1 to treatment with low-dose clonidine or placebo for 9 weeks and monitored for 30 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.

Interventions Clonidine hydrochloride capsules (25 µg or 50 µg twice daily for body weight <35 kg or >35 kg, respectively) vs placebo capsules for 9 weeks.

Main Outcomes and Measures Number of steps per day.

Results At baseline, patients with CFS had a lower number of steps per day (P < .001), digit span backward score (P = .002), and urinary cortisol to creatinine ratio (P = .001), and a higher fatigue score (P < .001), heart rate responsiveness (P = .02), plasma norepinephrine level (P < .001), and serum C-reactive protein concentration (P = .04) compared with healthy controls. There were no significant differences regarding blood microbiology evaluation. During intervention, the clonidine group had a lower number of steps per day (mean difference, −637 steps; P = .07), lower plasma norepinephrine level (mean difference, −42 pg/mL; P = .01), and lower serum C-reactive protein concentration (mean ratio, 0.69; P = .02) compared with the CFS placebo group.

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.

Web | DOI | JAMA Pediatrics
(Older paper which we have discussed before, putting it here to make it easier to find)

 

[hotblack]

Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus-pituitary-adrenal axis function

We have no evidence of any of this do we?

The Wikipedia page on Clonidine has this to say

Clonidine is a non-selective α2 adrenoreceptor and imidazoline receptor agonist that reduces sympathetic nervous system output from the brainstem, which lowers peripheral vascular resistance, heart rate and plasma renin activity, thereby reducing systolic and diastolic blood pressure as a consequence.

And also

α2 adrenoreceptor agonists (i.e., clonidine and guanfacine) are one class of non-stimulant medications that treat ADHD by stimulating receptors expressed in the prefrontal cortex, thereby enhancing cognitive control of behavior. Clonidine acts non-selectively at α2A, α2B and α2C receptor subtypes across the central nervous system, whereas guanfacine is selective for postsynaptic α2A adrenoreceptors, a difference that is believed to be partially responsible for clonidine's greater propensity for sedative and hypotensive side effects.

There’s an extensive pharmacology section including this

α2 adrenoceptors are also expressed on axon terminals that release several other neurotransmitters (i.e., serotonin, dopamine, acetylcholine, GABA, and glutamate), and their activation can suppress release at these synapses as well

There’s more potentially useful detail on how it dies this on the linked page.

So of it were to help people in some way it could be just as likely to have some other downstream knock on impact on brain activity or networks in areas we’ve been recently looking at than the reasons outlined in the paper? All speculation of course but so is the paper.

 

[fst]

I wonder what the effect of clonidine would have been on healthy controls? It is described as quite sedating. Maybe also a reduction in steps?

I could imagine that the increased adrenergic tone (if it exists) is a compensation mechanism and suppressing it makes people worse.

I'm thinking a long the lines of vascular disregulation or desensitized adrenergic, receptors which at the moment is speculation of course.

 

[ScoutB]

We have no evidence of any of this do we?

Yes, to be clear, this paper has come up before because it was one of the more concrete attempts to test the anxiety/sympathetic-overactivation 'hypothesis' of ME/CFS -- and it seems to have failed.

I wonder what the effect of clonidine would have been on healthy controls? It is described as quite sedating. Maybe also a reduction in steps?

I could imagine that the increased adrenergic tone (if it exists) is a compensation mechanism and suppressing it makes people worse.

Yes agree with both these thoughts. I kinda suspect results in controls would be similar. And I find stimulants improve my symptoms so I am biased for the 'compensation' interpretation too

 

[hotblack]

Interesting @fst and thanks @ScoutB

I remember there have been various studies and around adrenergic receptors, with mixed evidence and mixed views of those studies, but I do wonder if when we eventually know what’s causing me/cfs some of these will make more sense, but perhaps in a different way than they originally did. Some may still just not add up too of course.

 

[fst]

Yes agree with both these thoughts. I kinda suspect results in controls would be similar. And I find stimulants improve my symptoms so I am biased for the 'compensation' interpretation too

Personally speaking, I am convinced that there is increased adrenergic tone in ME/CFS, even though the scientific evidence is still sparse. Increased heart rates during PEM and adrenaline dumps are among the most universal anecdotes reported by patients.

During my slide into severe ME/CFS, I wore a smartwatch and my daytime resting heart rate increased from 65 to 75 bpm, while my HRV roughly halved.

Another hint at adrenaline is the presence of cold, sweaty hands and feet, which get worse with even the slightest exertion and improve in the evening.

Interestingly, after immunoadsorption, I got my old heart rate back for about a month, but otherwise did not feel much better. Which is interesting given that IA doesn't seem to do anything at all. Maybe that effect was related to the crash, who knows.

The question remains whether this is a compensatory mechanism or not, and if so, for what? This paper may very cautiously hint at compensation.